Brg1和Brm对CAMs和ET-1的转录调控及其在低氧性肺动脉高压中的作用和机制研究
|
摘要
研究背景：
低氧性肺动脉高压(Hypoxia Pulmonary Hypertension，HPH)是由低氧引起的以持续肺动脉压力增高、肺血管结构改建，并伴有右心室肥大的慢性进行性疾病，是高原心脏病和肺源性心脏病发病的中心环节。HPH的形成是一个复杂的病理生理过程，已有研究表明，炎症免疫反应和血管活性物质分泌失调是其中的两个重要机制。炎症免疫细胞在血管壁的黏附聚集是炎症发生的起始环节，而血管内皮细胞中ICAM-1、VCAM-1和E-selectin等细胞黏附分子(cell adhesion molecules，CAMs)是其中的关键作用分子。低氧时内皮细胞中CAMs基因转录激活，促进循环免疫细胞的黏附聚集和血管周围炎症微环境的形成，引起肺动脉高压和肺血管结构改建。内皮素1(Endothelin1，ET-1)是内皮细胞分泌的缩血管作用最强的活性多肽，低氧可诱导ET-1表达上调，参与HPH的发生。目前已知，CAMs和ET-1基因表达受核因子kB(Nuclear factor kappaB，NF-kB)、低氧诱导因子1α(Hypoxia inducible factor1α，HIF-1α)和巨核细胞性白血病因子1(Megakaryocytic leukemia1，MKL1)等转录因子调节。低氧时上述转录因子进入核内增多，与启动子序列特异结合，启动基因转录和表达。
真核细胞的DNA由组蛋白包裹形成核小体乃至染色体，基因转录时首先需要打开核小体结构，暴露启动子序列，即染色质重构。Brahma-related gene1(Brg1)和brahma(Brm)是哺乳动物染色质重构复合物SWI(mating-type switching)/SNF(sucrosefermentation)的核心ATP酶亚单位，两者结构相似、功能互补。Brg1和Brm可以水解ATP释放能量实现对核小体的重排和置换，从而调节靶基因的转录。研究表明，Brg1和Brm在胚胎发育过程中的血管平衡维持和应激相关疾病发生中都具有重要作用。最新研究发现，HIF-1α可以招募Brg1和Brm至其靶基因，参与细胞低氧反应，但Brg1和Brm是否及如何参与低氧诱导的CAMs及ET-1转录调控，进而促进HPH的发生和发展，迄今未见报道。
因此，本研究在明确低氧诱导肺血管及内皮细胞中Brg1和Brm基因表达的基础上，研究其对内皮细胞CAMs和ET-1转录调控的作用及机制；特异干扰内皮细胞中的Brg1和Brm，进一步探讨Brg1和Brm在肺血管结构改建和HPH形成中的作用和机制。为干预或预防HPH提供新的思路和有效靶点。
方法：
1.模拟海拔5000m高原28d复制雄性SD大鼠HPH模型，分离肺动脉；将人肺动脉内皮细胞(Human pulmonary arterial endothelial cell，HPEC)和人脐静脉内皮细胞(Human umbilical vein endothelial cell，HUVEC)低氧(1%O2)处理24h；RT-qPCR及WB法检测肺动脉及内皮细胞中Brg1和Brm基因的mRNA及蛋白表达。
2.通过外源性质粒转染内皮细胞(HPEC、HUVEC)过表达或siRNA转染干扰内源性的Brg1和Brm基因，采用报告基因法检测CAMs启动子转录活性；采用RT-qPCR及WB方法检测CAMs基因的mRNA及蛋白表达；采用细胞黏附实验检测内皮细胞的黏附功能。为了进一步探讨低氧时Brg1和Brm激活CAMs转录的机制，采用染色质免疫共沉淀(Chromatin immunoprecipitation，CHIP)方法检测低氧后Brg1和Brm与内皮细胞中CAMs启动子的结合水平；siRNA转染干扰Brg1和Brm后，进一步运用CHIP方法检测NF-kB/p65与CAMs启动子的结合水平，同时运用CHIP方法检测CAMs启动子周围AcH3和H3K4M3等组蛋白修饰变化。
3.内皮细胞(HPEC、HUVEC)中外源性质粒转染过表达或siRNA干扰内源性的Brg1和Brm基因，采用报告基因法检测ET-1启动子的转录活性；采用RT-qPCR及ELISA法检测ET-1的mRNA表达；采用CHIP方法检测低氧后特异结合在内皮细胞(HUVEC) ET-1启动子上的Brg1和Brm以及MKL1蛋白水平；siRNA转染干扰Brg1和Brm后，采用CHIP方法检测ET-1启动子周围AcH3和H3K4M3等组蛋白修饰变化。
4.将雄性C57/BL6小鼠随机分为常氧组、低氧组、低氧对照病毒组和低氧Brg1/Brm干扰病毒组。常氧组和低氧组给予生理盐水，低氧对照病毒组给予对照病毒液，低氧Brg1/Brm干扰病毒组尾静脉注射内皮细胞特异性Brg1/Brm干扰质粒慢病毒敲减Brg1和Brm基因表达；低氧各组置于低压氧舱内模拟海拔5000m低氧处理28d复制小鼠HPH模型。采用导管法检测右心室血流动力学指标；采用HE染色及免疫组化(Immunohistochemisty， IHC)染色检测肺血管改建，采用免疫荧光(Immunofluorescence，IF)法检测肺血管内皮细胞中Brg1和Brm的表达以及肺血管周围炎症细胞浸润；采用RT-qPCR法检测肺组织中CAMs的表达；采用ELISA法检测肺组织匀浆IL-1β、IL-6、MCP-1、TNF-α等炎症因子的表达；采用CHIP法检测低氧后肺组织中Brg1和Brm与ICAM-1启动子的结合水平。
结果：
1.低氧可显著上调SD大鼠的肺动脉(5000m，28d)和内皮细胞(HPEC、HUVEC，1%O2，24h) Brg1和Brm的mRNA和蛋白表达。
2.内皮细胞(HPEC、HUVEC)中过表达Brg1和Brm能显著增强低氧(1%O2，24h)诱导的CAMs启动子转录活性，且该作用依赖于其酶催化活性；过表达Brg1和Brm显著上调内皮细胞中内源性CAMs的mRNA和蛋白表达；敲减Brg1和Brm基因可显著抑制低氧诱导的CAMs启动子转录活性增强和内皮细胞内源性CAMs表达，且内皮细胞与白细胞的黏附作用降低。CHIP实验显示低氧能显著增加Brg1和Brm在内皮细胞CAMs启动子上p65的结合区域的结合；干扰内皮细胞中的Brg1和Brm能显著抑制p65与CAMs启动子的结合，CAMs启动子周围AcH3和H3K4Me3等具有转录活化作用的组蛋白也显著减少，Pol II的招募也显著减少。
3.内皮细胞(HUVEC)中过表达Brg1和Brm能显著增强低氧诱导的ET-1启动子转录活性，酶失活的Brg1和Brm并不增强ET-1启动子转录活性；干扰内皮细胞(HPEC、HUVEC)中的Brg1和Brm能显著抑制ET-1启动子的转录活性以及ET-1的表达和分泌；CHIP实验发现低氧能显著增加Brg1和Brm以及MKL1在内皮细胞(HUVEC) ET-1启动子上的结合；干扰Brg1和Brm后，ET-1启动子周围AcH3和H3K4Me3等具有转录活化作用的组蛋白也显著减少。
4.成功构建HPH小鼠模型，IF结果显示干扰病毒组小鼠肺血管内皮细胞中Brg1和Brm的表达显著降低；伴随着肺血管内皮细胞中Brg1和Brm的表达抑制，肺组织中CAMs基因的mRNA表达也显著降低，小鼠右心室收缩压和肥厚指数也显著降低，肺血管厚度显著变薄，肺血管重构显著改善，肺血管周围炎症细胞浸润显著减少，肺组织匀浆中IL-1β、IL-6、MCP-1的分泌显著降低。CHIP结果显示HPH小鼠肺组织中的Brg1和Brm被更多的招募到ICAM-1的启动子上。
结论：
1. HPH大鼠肺血管中Brg1和Brm基因表达增多，内皮细胞可能是其中一种重要效应细胞；
2. Brg1和Brm介导低氧内皮细胞中CAMs转录和表达，参与调节低氧内皮细胞与白细胞的黏附作用，其作用机制依赖与NF-kB/p65的相互作用，以及对CAMs启动子周围的组蛋白修饰的影响；
3. Brg1和Brm参与调控低氧内皮细胞中ET-1转录和表达，其作用机制依赖与MKL1的相互作用及其对ET-1启动子周围组蛋白修饰的调节作用；
4.特异干扰HPH小鼠内皮细胞中Brg1和Brm基因，可显著降低右心室收缩压、抑制肺血管重构和右心室肥厚；其机制与CAMs及ET-1转录抑制并表达降低、肺血管周围炎症细胞浸润减少和炎症细胞因子表达降低密切相关；
5.肺血管内皮细胞中的Brg1和Brm基因在HPH的形成中发挥重要作用，有望成为干预或防治HPH的有效靶点。
Background：
Hypoxia Pulmonary Hypertension is a chronic progressive disease which caused bylow oxygen, characterized by elevated pulmonary hypertrophy and pulmonary vascularremodeling and associated with right ventricular hypertrophy. The formation of HPH is acomplex pathophysiological process. Pulmonary vasoconstriction, inflammation, cellproliferation and transformation, all of them were involved in HPH. Hypoxic pulmonaryvasoconstrictions mediated by endothelin, which secrete from vascular endothelial cells,play an important role in the development of HPH. In addition, inflammation may play animportant role in this process. Elevated inflammation is invariably initiated by theaggregation and adhesion of immune cells on the vessel wall. Pivotal to this process is theadhesion of leukocytes to the vessel wall facilitated by the up-regulation of cell adhesionmolecules (CAMs) in vascular endothelial cells. Therefore, accelerated transcription ofCAMs genes in hypoxic endothelial cells represents a key event that foretells enhancedleukocyte adhesion, perpetuated vascular inflammation, and eventually the development ofHPH. As we know，CAMs and ET-1transactivation were regulated by nuclear factor kappaB (NF-kB), hypoxia inducible factor1α (HIF-1α) and megakaryocytic leukemia1(MKL1).These transcription factors combined with specific promoter sequence under hypoxia, tostart CAMs and ET-1transcription and expression. But the epigenetic switch that dictatesCAMs and ET-1transactivation in response to hypoxia in endothelial cells leading up toHPH is not fully appreciated.
Unlike the prokaryotic organisms, eukaryotic genes are wrapped by histones intoindividual nucleosomes to form chromatin that needs to be unfolded in order for the basictranscription machinery to gain access. Brahma-related gene1(Brg1) and brahma (Brm)are the catalytic components of the mammalian chromatin remodelling complex playingimportant roles in maintaining vascular homoeostasis in embryogenesis and promoting a pathogenic agenda under stress conditions. This remodelling complex utilizes ATP tomobilize nucleosomes and alter transcription. Brg1and Brm playing important roles inmaintaining vascular homeostasis in embryogenesis and promoting a pathogenic agendaunder stress conditions. Brg1and Brm were also involved in cellular hypoxia reactionwhich was mediated by HIF-1alpha. However, whether Brg1/Brm is upregulated byhypoxia stress and accelerated the CAMs and ET-1genes in hypoxic endothelial cells. Andthe transcription mechanism of CAMs and ET-1involved in HPH development is not fullyunderstood.
Therefore, this study was undertaken to observe the expression levels of Brg1and Brmin isolated pulmonary arteries of HPH rats and cultured human endothelial cells. Andobserve the regulation of transactivation of CAMs and ET-1genes in endothelial cells inresponse to hypoxic stress. In addition, we constructed the endothelial-specific vector thatencodes shRNA targeting both Brg1and Brm, to test the role of Brg1and Brm in thehypoxia-induced vascular inflammation and pulmonary vascular remodeling. As such,targeting Brg1/Brm in endothelial cells may yield promising strategies in the interventionand/or prevention of HPH.
Methods：
1. SD rats were housed in a hypobaric hypoxia chamber (Simulated altitude:5000m)for4weeks to induce hypoxic pulmonary hypertension. Pulmonary arteries were thenisolated to measure the expression of Brg1and Brm by RT-qPCR and Western blot. HPEC、HUVEC were exposed to1%O2, the expressions of Brg1and Brm were also detected.
2. Over-expression of exogenous Brg1and Brm or knocked down the expression ofendogenous Brg1and Brm using siRNA in endothelial cells. The promoter activities ofCAM genes induced by hypoxia were detected by reporter assays. The endogenous CAMsmessages induced by hypoxia were also detected by RT-qPCR and Western blot. In vitro,adhesion assay was used to detect the interaction between endothelial cells and leukocytes.To further explore the interplay between p65and Brg1/Brm in hypoxia-inducedtransactivation of CAMs genes, we knocked down the expression of p65or Brg1/Brm withsiRNA in endothelial cells. ChIP assay to detect the combination of NF-kB/p65orBrg1/Brm with CAMs promoter. We also detect the histone modifications surrounding theCAMs promoters by ChIP assay
3. Over-expression of exogenous Brg1and Brm or knocked down the expression ofendogenous Brg1and Brm using siRNA in endothelial cells. The promoter activitie of ET-1gene induced by hypoxia was detected by reporter assays. The endogenous ET-1messagesinduced by hypoxia were also detected by RT-qPCR and ELISA. ChIP assay was used todetect the combination of Brg1/Brm with ET-1promoter. The histone modificationssurrounding the ET-1promoter was also detectd by ChIP assay.
4. Male C57/BL6mice were randomly divided into normoxia group, hypoxia group,control virus group and interfere virus group. The last three group were housed in ahypobaric hypoxia chamber (Simulated altitude:5000m) for4weeks to induce hypoxicpulmonary hypertension. In the meantime, these mice were injected via tail veinphysiological saline or lentiviral particles carrying a SCR or endothelial-specific vector thatencodes shRNA targeting both Brg1and Brm. Hemodynamic and pulmonarypathomorphology data were gathered. The hypertrophy of right ventricle was evaluated bythe ratio of weight of the right ventricle (RV) to the weight of the left ventricle (LV) plusventricular septal (VS) and RV weight over body weight. The remodelling of pulmonaryvasculature, as measured by vessel wall thickness, was detected by HE or IHC. Therecruitment of immune cells to the vessels was detected by IF. The activities of cytokineIL-1β、IL-6、MCP-1and TNF-α in lung tissue homogenate extracts was detected by ELISA.The combination of Brg1/Brm with ICAM-1promoter in lung tissue was also detectd byChIP assay
Results：
1. The levels of Brg1and Brm were significantly elevated in HPH rats as opposed toage-and sex-matched control rats. Exposure to1%O2caused an up-regulation in themessage levels of Brg1and Brm in both HUVEC and HPECs.
2. Brg1and Brm were able to enhance the activation of CAMs promoters by hypoxia.Point mutations (ED, enzyme dead) that interfere with the catalytic domain deprived Brg1and Brm of their ability to activate CAMs promoters under hypoxic conditions. Moreimportantly, over-expression of Brg1and Brm led to a marked increase in the levels ofendogenous adhesion molecules. When knocked down the expression of endogenous Brg1and Brm using siRNA, induction of CAMs promoter activities by hypoxia was severelycrippled. Furthermore, the induction of endogenous CAMs messages by hypoxia was also limited in both HUVEC and HPEC. In vitro adhesion assay also revealed that theinteraction between endothelial cells and leukocytes was weakened by the elimination ofBrg1and Brm. ChIP assay indicates there was a dramatic increase in the occupancies ofBrg1and Brm on the promoter region of the CAMs genes spanning the NF-kB site underhypoxic conditions. Consistent with these observations, re-ChIP assays demonstrate thathypoxia promoted the interaction between Brg1/Brm and NF-kB/p65on the CAMspromoters. Reciprocally, depletion of Brg1or Brm negatively affected the binding of p65on all three CAMs promoters. Ablation of Brg1and Brm greatly reduced the levels of AcH3and H3K4Me3, all of which herald transcriptional activation, on the CAMs promoterregions. As a result, the recruitment of RNA polymerase II (Pol II) was hampered probablyleading to a decelerated transcription rate.
3. Brg1and Brm were able to enhance the activation of ET-1promoters by hypoxia,which require the enzymatic activity. When knocked down the expression of endogenousBrg1and Brm using siRNA, induction of ET-1promoter activities by hypoxia was severelycrippled. Furthermore, the induction of endogenous ET-1messages was also limited inendothelial cells. ChIP assay indicates there was a dramatic increase in the occupancies ofBrg1and Brm on the promoter region of the ET-1gene under hypoxic conditions. Ablationof Brg1and Brm greatly reduced the levels of AcH3, H3K4Me2and H3K4Me3around theET-1promoter.
4. In the mice HPH model, Immunofluorescence staining revealed that the expressionof Brg1and Brm was effectively reduced in the pulmonary endothelium by the viralparticles which contains endothelial-specific vector that encodes shRNA targeting bothBrg1and Brm. Correction of HPH by Brg1/Brm depletion was accompanied by thedown-regulation of all three CAM molecules in pulmonary arteries. As a result, elevation ofright ventricular pressure (RVSP) was significantly relieved by endothelial-specificBrg1/Brm silencing, as was as the hypertrophy of right ventricle. And, there was decreasedrecruitment of immune cells to the vessels. Furthermore, remodelling of pulmonaryvasculature, as measured by vessel wall thickness, was suppressed in mice injected withendo-siBrg1/siBrm compared with mice injected with control shRNA. Also the activities ofIL-1β, IL-6and MCP-1were inhibited remarkably. More importantly, hypoxia recruitedmore Brg1and Brm to the ICAM-1promoter in pulmonary arteries isolated from HPH mice when compared with the control mice.
Conclusion：
1. The expression of Brg1and Brm fluctuates in HPH rats and endothelial cells inresponse to oxygen tension indicative of a potential role for Brg1/Brm in endothelialmalfunction and pathogenesis of HPH.
2. Brg1and Brm are both sufficient and necessary for hypoxia-induced CAMstransactivation and leukocyte adhesionin vitro. Brg1/Brm/p65complex forms on the CAMspromoters in response to hypoxia to activate transcription in endothelial cells. Brg1andBrm can form a crosstalk with the histone modification machinery to influencehypoxia-induced CAMs transactivation.
3. Brg1and Brm are indispensable for hypoxia-induced transactivation of the ET-1gene. They can form a crosstalk with the histone modification machinery to influencehypoxia-induced ET-1transactivation.
4. Endothelial-specific Brg1/Brm silencing stalled remodelling of pulmonaryvasculature and development of HPH, likely owing to the normalization of endothelialfunction and pulmonary inflammation in vivo.
5. As such, targeting Brg1and Brm in endothelial cells may yield promising strategiesin the intervention and/or prevention of HPH.
低氧性肺动脉高压(Hypoxia Pulmonary Hypertension，HPH)是由低氧引起的以持续肺动脉压力增高、肺血管结构改建，并伴有右心室肥大的慢性进行性疾病，是高原心脏病和肺源性心脏病发病的中心环节。HPH的形成是一个复杂的病理生理过程，已有研究表明，炎症免疫反应和血管活性物质分泌失调是其中的两个重要机制。炎症免疫细胞在血管壁的黏附聚集是炎症发生的起始环节，而血管内皮细胞中ICAM-1、VCAM-1和E-selectin等细胞黏附分子(cell adhesion molecules，CAMs)是其中的关键作用分子。低氧时内皮细胞中CAMs基因转录激活，促进循环免疫细胞的黏附聚集和血管周围炎症微环境的形成，引起肺动脉高压和肺血管结构改建。内皮素1(Endothelin1，ET-1)是内皮细胞分泌的缩血管作用最强的活性多肽，低氧可诱导ET-1表达上调，参与HPH的发生。目前已知，CAMs和ET-1基因表达受核因子kB(Nuclear factor kappaB，NF-kB)、低氧诱导因子1α(Hypoxia inducible factor1α，HIF-1α)和巨核细胞性白血病因子1(Megakaryocytic leukemia1，MKL1)等转录因子调节。低氧时上述转录因子进入核内增多，与启动子序列特异结合，启动基因转录和表达。
真核细胞的DNA由组蛋白包裹形成核小体乃至染色体，基因转录时首先需要打开核小体结构，暴露启动子序列，即染色质重构。Brahma-related gene1(Brg1)和brahma(Brm)是哺乳动物染色质重构复合物SWI(mating-type switching)/SNF(sucrosefermentation)的核心ATP酶亚单位，两者结构相似、功能互补。Brg1和Brm可以水解ATP释放能量实现对核小体的重排和置换，从而调节靶基因的转录。研究表明，Brg1和Brm在胚胎发育过程中的血管平衡维持和应激相关疾病发生中都具有重要作用。最新研究发现，HIF-1α可以招募Brg1和Brm至其靶基因，参与细胞低氧反应，但Brg1和Brm是否及如何参与低氧诱导的CAMs及ET-1转录调控，进而促进HPH的发生和发展，迄今未见报道。
因此，本研究在明确低氧诱导肺血管及内皮细胞中Brg1和Brm基因表达的基础上，研究其对内皮细胞CAMs和ET-1转录调控的作用及机制；特异干扰内皮细胞中的Brg1和Brm，进一步探讨Brg1和Brm在肺血管结构改建和HPH形成中的作用和机制。为干预或预防HPH提供新的思路和有效靶点。
方法：
1.模拟海拔5000m高原28d复制雄性SD大鼠HPH模型，分离肺动脉；将人肺动脉内皮细胞(Human pulmonary arterial endothelial cell，HPEC)和人脐静脉内皮细胞(Human umbilical vein endothelial cell，HUVEC)低氧(1%O2)处理24h；RT-qPCR及WB法检测肺动脉及内皮细胞中Brg1和Brm基因的mRNA及蛋白表达。
2.通过外源性质粒转染内皮细胞(HPEC、HUVEC)过表达或siRNA转染干扰内源性的Brg1和Brm基因，采用报告基因法检测CAMs启动子转录活性；采用RT-qPCR及WB方法检测CAMs基因的mRNA及蛋白表达；采用细胞黏附实验检测内皮细胞的黏附功能。为了进一步探讨低氧时Brg1和Brm激活CAMs转录的机制，采用染色质免疫共沉淀(Chromatin immunoprecipitation，CHIP)方法检测低氧后Brg1和Brm与内皮细胞中CAMs启动子的结合水平；siRNA转染干扰Brg1和Brm后，进一步运用CHIP方法检测NF-kB/p65与CAMs启动子的结合水平，同时运用CHIP方法检测CAMs启动子周围AcH3和H3K4M3等组蛋白修饰变化。
3.内皮细胞(HPEC、HUVEC)中外源性质粒转染过表达或siRNA干扰内源性的Brg1和Brm基因，采用报告基因法检测ET-1启动子的转录活性；采用RT-qPCR及ELISA法检测ET-1的mRNA表达；采用CHIP方法检测低氧后特异结合在内皮细胞(HUVEC) ET-1启动子上的Brg1和Brm以及MKL1蛋白水平；siRNA转染干扰Brg1和Brm后，采用CHIP方法检测ET-1启动子周围AcH3和H3K4M3等组蛋白修饰变化。
4.将雄性C57/BL6小鼠随机分为常氧组、低氧组、低氧对照病毒组和低氧Brg1/Brm干扰病毒组。常氧组和低氧组给予生理盐水，低氧对照病毒组给予对照病毒液，低氧Brg1/Brm干扰病毒组尾静脉注射内皮细胞特异性Brg1/Brm干扰质粒慢病毒敲减Brg1和Brm基因表达；低氧各组置于低压氧舱内模拟海拔5000m低氧处理28d复制小鼠HPH模型。采用导管法检测右心室血流动力学指标；采用HE染色及免疫组化(Immunohistochemisty， IHC)染色检测肺血管改建，采用免疫荧光(Immunofluorescence，IF)法检测肺血管内皮细胞中Brg1和Brm的表达以及肺血管周围炎症细胞浸润；采用RT-qPCR法检测肺组织中CAMs的表达；采用ELISA法检测肺组织匀浆IL-1β、IL-6、MCP-1、TNF-α等炎症因子的表达；采用CHIP法检测低氧后肺组织中Brg1和Brm与ICAM-1启动子的结合水平。
结果：
1.低氧可显著上调SD大鼠的肺动脉(5000m，28d)和内皮细胞(HPEC、HUVEC，1%O2，24h) Brg1和Brm的mRNA和蛋白表达。
2.内皮细胞(HPEC、HUVEC)中过表达Brg1和Brm能显著增强低氧(1%O2，24h)诱导的CAMs启动子转录活性，且该作用依赖于其酶催化活性；过表达Brg1和Brm显著上调内皮细胞中内源性CAMs的mRNA和蛋白表达；敲减Brg1和Brm基因可显著抑制低氧诱导的CAMs启动子转录活性增强和内皮细胞内源性CAMs表达，且内皮细胞与白细胞的黏附作用降低。CHIP实验显示低氧能显著增加Brg1和Brm在内皮细胞CAMs启动子上p65的结合区域的结合；干扰内皮细胞中的Brg1和Brm能显著抑制p65与CAMs启动子的结合，CAMs启动子周围AcH3和H3K4Me3等具有转录活化作用的组蛋白也显著减少，Pol II的招募也显著减少。
3.内皮细胞(HUVEC)中过表达Brg1和Brm能显著增强低氧诱导的ET-1启动子转录活性，酶失活的Brg1和Brm并不增强ET-1启动子转录活性；干扰内皮细胞(HPEC、HUVEC)中的Brg1和Brm能显著抑制ET-1启动子的转录活性以及ET-1的表达和分泌；CHIP实验发现低氧能显著增加Brg1和Brm以及MKL1在内皮细胞(HUVEC) ET-1启动子上的结合；干扰Brg1和Brm后，ET-1启动子周围AcH3和H3K4Me3等具有转录活化作用的组蛋白也显著减少。
4.成功构建HPH小鼠模型，IF结果显示干扰病毒组小鼠肺血管内皮细胞中Brg1和Brm的表达显著降低；伴随着肺血管内皮细胞中Brg1和Brm的表达抑制，肺组织中CAMs基因的mRNA表达也显著降低，小鼠右心室收缩压和肥厚指数也显著降低，肺血管厚度显著变薄，肺血管重构显著改善，肺血管周围炎症细胞浸润显著减少，肺组织匀浆中IL-1β、IL-6、MCP-1的分泌显著降低。CHIP结果显示HPH小鼠肺组织中的Brg1和Brm被更多的招募到ICAM-1的启动子上。
结论：
1. HPH大鼠肺血管中Brg1和Brm基因表达增多，内皮细胞可能是其中一种重要效应细胞；
2. Brg1和Brm介导低氧内皮细胞中CAMs转录和表达，参与调节低氧内皮细胞与白细胞的黏附作用，其作用机制依赖与NF-kB/p65的相互作用，以及对CAMs启动子周围的组蛋白修饰的影响；
3. Brg1和Brm参与调控低氧内皮细胞中ET-1转录和表达，其作用机制依赖与MKL1的相互作用及其对ET-1启动子周围组蛋白修饰的调节作用；
4.特异干扰HPH小鼠内皮细胞中Brg1和Brm基因，可显著降低右心室收缩压、抑制肺血管重构和右心室肥厚；其机制与CAMs及ET-1转录抑制并表达降低、肺血管周围炎症细胞浸润减少和炎症细胞因子表达降低密切相关；
5.肺血管内皮细胞中的Brg1和Brm基因在HPH的形成中发挥重要作用，有望成为干预或防治HPH的有效靶点。
Background：
Hypoxia Pulmonary Hypertension is a chronic progressive disease which caused bylow oxygen, characterized by elevated pulmonary hypertrophy and pulmonary vascularremodeling and associated with right ventricular hypertrophy. The formation of HPH is acomplex pathophysiological process. Pulmonary vasoconstriction, inflammation, cellproliferation and transformation, all of them were involved in HPH. Hypoxic pulmonaryvasoconstrictions mediated by endothelin, which secrete from vascular endothelial cells,play an important role in the development of HPH. In addition, inflammation may play animportant role in this process. Elevated inflammation is invariably initiated by theaggregation and adhesion of immune cells on the vessel wall. Pivotal to this process is theadhesion of leukocytes to the vessel wall facilitated by the up-regulation of cell adhesionmolecules (CAMs) in vascular endothelial cells. Therefore, accelerated transcription ofCAMs genes in hypoxic endothelial cells represents a key event that foretells enhancedleukocyte adhesion, perpetuated vascular inflammation, and eventually the development ofHPH. As we know，CAMs and ET-1transactivation were regulated by nuclear factor kappaB (NF-kB), hypoxia inducible factor1α (HIF-1α) and megakaryocytic leukemia1(MKL1).These transcription factors combined with specific promoter sequence under hypoxia, tostart CAMs and ET-1transcription and expression. But the epigenetic switch that dictatesCAMs and ET-1transactivation in response to hypoxia in endothelial cells leading up toHPH is not fully appreciated.
Unlike the prokaryotic organisms, eukaryotic genes are wrapped by histones intoindividual nucleosomes to form chromatin that needs to be unfolded in order for the basictranscription machinery to gain access. Brahma-related gene1(Brg1) and brahma (Brm)are the catalytic components of the mammalian chromatin remodelling complex playingimportant roles in maintaining vascular homoeostasis in embryogenesis and promoting a pathogenic agenda under stress conditions. This remodelling complex utilizes ATP tomobilize nucleosomes and alter transcription. Brg1and Brm playing important roles inmaintaining vascular homeostasis in embryogenesis and promoting a pathogenic agendaunder stress conditions. Brg1and Brm were also involved in cellular hypoxia reactionwhich was mediated by HIF-1alpha. However, whether Brg1/Brm is upregulated byhypoxia stress and accelerated the CAMs and ET-1genes in hypoxic endothelial cells. Andthe transcription mechanism of CAMs and ET-1involved in HPH development is not fullyunderstood.
Therefore, this study was undertaken to observe the expression levels of Brg1and Brmin isolated pulmonary arteries of HPH rats and cultured human endothelial cells. Andobserve the regulation of transactivation of CAMs and ET-1genes in endothelial cells inresponse to hypoxic stress. In addition, we constructed the endothelial-specific vector thatencodes shRNA targeting both Brg1and Brm, to test the role of Brg1and Brm in thehypoxia-induced vascular inflammation and pulmonary vascular remodeling. As such,targeting Brg1/Brm in endothelial cells may yield promising strategies in the interventionand/or prevention of HPH.
Methods：
1. SD rats were housed in a hypobaric hypoxia chamber (Simulated altitude:5000m)for4weeks to induce hypoxic pulmonary hypertension. Pulmonary arteries were thenisolated to measure the expression of Brg1and Brm by RT-qPCR and Western blot. HPEC、HUVEC were exposed to1%O2, the expressions of Brg1and Brm were also detected.
2. Over-expression of exogenous Brg1and Brm or knocked down the expression ofendogenous Brg1and Brm using siRNA in endothelial cells. The promoter activities ofCAM genes induced by hypoxia were detected by reporter assays. The endogenous CAMsmessages induced by hypoxia were also detected by RT-qPCR and Western blot. In vitro,adhesion assay was used to detect the interaction between endothelial cells and leukocytes.To further explore the interplay between p65and Brg1/Brm in hypoxia-inducedtransactivation of CAMs genes, we knocked down the expression of p65or Brg1/Brm withsiRNA in endothelial cells. ChIP assay to detect the combination of NF-kB/p65orBrg1/Brm with CAMs promoter. We also detect the histone modifications surrounding theCAMs promoters by ChIP assay
3. Over-expression of exogenous Brg1and Brm or knocked down the expression ofendogenous Brg1and Brm using siRNA in endothelial cells. The promoter activitie of ET-1gene induced by hypoxia was detected by reporter assays. The endogenous ET-1messagesinduced by hypoxia were also detected by RT-qPCR and ELISA. ChIP assay was used todetect the combination of Brg1/Brm with ET-1promoter. The histone modificationssurrounding the ET-1promoter was also detectd by ChIP assay.
4. Male C57/BL6mice were randomly divided into normoxia group, hypoxia group,control virus group and interfere virus group. The last three group were housed in ahypobaric hypoxia chamber (Simulated altitude:5000m) for4weeks to induce hypoxicpulmonary hypertension. In the meantime, these mice were injected via tail veinphysiological saline or lentiviral particles carrying a SCR or endothelial-specific vector thatencodes shRNA targeting both Brg1and Brm. Hemodynamic and pulmonarypathomorphology data were gathered. The hypertrophy of right ventricle was evaluated bythe ratio of weight of the right ventricle (RV) to the weight of the left ventricle (LV) plusventricular septal (VS) and RV weight over body weight. The remodelling of pulmonaryvasculature, as measured by vessel wall thickness, was detected by HE or IHC. Therecruitment of immune cells to the vessels was detected by IF. The activities of cytokineIL-1β、IL-6、MCP-1and TNF-α in lung tissue homogenate extracts was detected by ELISA.The combination of Brg1/Brm with ICAM-1promoter in lung tissue was also detectd byChIP assay
Results：
1. The levels of Brg1and Brm were significantly elevated in HPH rats as opposed toage-and sex-matched control rats. Exposure to1%O2caused an up-regulation in themessage levels of Brg1and Brm in both HUVEC and HPECs.
2. Brg1and Brm were able to enhance the activation of CAMs promoters by hypoxia.Point mutations (ED, enzyme dead) that interfere with the catalytic domain deprived Brg1and Brm of their ability to activate CAMs promoters under hypoxic conditions. Moreimportantly, over-expression of Brg1and Brm led to a marked increase in the levels ofendogenous adhesion molecules. When knocked down the expression of endogenous Brg1and Brm using siRNA, induction of CAMs promoter activities by hypoxia was severelycrippled. Furthermore, the induction of endogenous CAMs messages by hypoxia was also limited in both HUVEC and HPEC. In vitro adhesion assay also revealed that theinteraction between endothelial cells and leukocytes was weakened by the elimination ofBrg1and Brm. ChIP assay indicates there was a dramatic increase in the occupancies ofBrg1and Brm on the promoter region of the CAMs genes spanning the NF-kB site underhypoxic conditions. Consistent with these observations, re-ChIP assays demonstrate thathypoxia promoted the interaction between Brg1/Brm and NF-kB/p65on the CAMspromoters. Reciprocally, depletion of Brg1or Brm negatively affected the binding of p65on all three CAMs promoters. Ablation of Brg1and Brm greatly reduced the levels of AcH3and H3K4Me3, all of which herald transcriptional activation, on the CAMs promoterregions. As a result, the recruitment of RNA polymerase II (Pol II) was hampered probablyleading to a decelerated transcription rate.
3. Brg1and Brm were able to enhance the activation of ET-1promoters by hypoxia,which require the enzymatic activity. When knocked down the expression of endogenousBrg1and Brm using siRNA, induction of ET-1promoter activities by hypoxia was severelycrippled. Furthermore, the induction of endogenous ET-1messages was also limited inendothelial cells. ChIP assay indicates there was a dramatic increase in the occupancies ofBrg1and Brm on the promoter region of the ET-1gene under hypoxic conditions. Ablationof Brg1and Brm greatly reduced the levels of AcH3, H3K4Me2and H3K4Me3around theET-1promoter.
4. In the mice HPH model, Immunofluorescence staining revealed that the expressionof Brg1and Brm was effectively reduced in the pulmonary endothelium by the viralparticles which contains endothelial-specific vector that encodes shRNA targeting bothBrg1and Brm. Correction of HPH by Brg1/Brm depletion was accompanied by thedown-regulation of all three CAM molecules in pulmonary arteries. As a result, elevation ofright ventricular pressure (RVSP) was significantly relieved by endothelial-specificBrg1/Brm silencing, as was as the hypertrophy of right ventricle. And, there was decreasedrecruitment of immune cells to the vessels. Furthermore, remodelling of pulmonaryvasculature, as measured by vessel wall thickness, was suppressed in mice injected withendo-siBrg1/siBrm compared with mice injected with control shRNA. Also the activities ofIL-1β, IL-6and MCP-1were inhibited remarkably. More importantly, hypoxia recruitedmore Brg1and Brm to the ICAM-1promoter in pulmonary arteries isolated from HPH mice when compared with the control mice.
Conclusion：
1. The expression of Brg1and Brm fluctuates in HPH rats and endothelial cells inresponse to oxygen tension indicative of a potential role for Brg1/Brm in endothelialmalfunction and pathogenesis of HPH.
2. Brg1and Brm are both sufficient and necessary for hypoxia-induced CAMstransactivation and leukocyte adhesionin vitro. Brg1/Brm/p65complex forms on the CAMspromoters in response to hypoxia to activate transcription in endothelial cells. Brg1andBrm can form a crosstalk with the histone modification machinery to influencehypoxia-induced CAMs transactivation.
3. Brg1and Brm are indispensable for hypoxia-induced transactivation of the ET-1gene. They can form a crosstalk with the histone modification machinery to influencehypoxia-induced ET-1transactivation.
4. Endothelial-specific Brg1/Brm silencing stalled remodelling of pulmonaryvasculature and development of HPH, likely owing to the normalization of endothelialfunction and pulmonary inflammation in vivo.
5. As such, targeting Brg1and Brm in endothelial cells may yield promising strategiesin the intervention and/or prevention of HPH.
引文
1高钰琪.高原军事医学.重庆：重庆出版社.2004
2Yidiz P. Molecular mechanisms of pulmonary hypertension. Clinica Chimica Acta. May2009;403(1-2):9-16.
Ward JP, McMurtry IF. Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension:new findings for an old problem. Curr Opin Pharmacol. Jun2009;9(3):287-296.
4Rabinovitch M, Bothwell T, Hayakawa BN, Williams WG, Trusler GA, Rowe RD, Olley PM, Cutz E: Pulmonary arteryendothelial abnormalities in patients with congenital heart defects and pulmonary hypertension. A correlation of lightwith scanning electron microscopy and transmission electron microscopy. Lab Invest1986,55(6):632-653.
5陈小容,邹霞英:缺氧性肺动脉高压大鼠肺血管内皮细胞的变化.中国病理生理杂志1996,12(6):608-611.
1Botto L, Beretta E, Daffara R, Miserocchi G, Palestini P: Biochemical and morphological changes in endothelial cellsin response to hypoxic interstitial edema. Respir Res2006,7:7.
2Bagnato A, Rosano L. Epithelial-mesenchymal transition in ovarian cancer progression: a crucial role for theendothelin axis. Cells Tissues Organs.2007;185(1-3):85-94.
3Li H, Chen SJ, Chen YF, et al. Enhanced endothelin-1and endothelin receptor gene expression in chronic hypoxia.Journal of applied physiology (Bethesda, Md.:1985). Sep1994;77(3):1451-1459.
4Rubens C, Ewert R, Halank M, et al. Big endothelin-1and endothelin-1plasma levels are correlated with the severityof primary pulmonary hypertension. Chest. Nov2001;120(5):1562-1569.
5Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1in pulmonary hypertension: marker ormediator of disease? Ann Intern Med. Mar151991;114(6):464-469.
6Yamashita K, Discher DJ, Hu J, Bishopric NH, Webster KA: Molecular regulation of the endothelin-1gene by hypoxia.Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP. J Biol Chem2001,276(16):12645-12653.
7Yang Y, Chen D, Yuan Z, et al. Megakaryocytic leukemia1(MKL1) ties the epigenetic machinery to hypoxia-inducedtransactivation of endothelin-1. Nucleic Acids Res. Jul12013;41(12):6005-6017.
8Savale L, Tu L, Rideau D, Izziki M, Maitre B, Adnot S, Eddahibi S: Impact of interleukin-6on hypoxia-inducedpulmonary hypertension and lung inflammation in mice. Respir Res2009,10:6.
9Burke DL, Frid MG, Kunrath CL, Karoor V, Anwar A, Wagner BD, Strassheim D, Stenmark KR: Sustained hypoxiapromotes the development of a pulmonary artery-specific chronic inflammatory microenvironment. Am J Physiol LungCell Mol Physiol2009,297(2):L238-250.
10Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB: Interleukin-6overexpression inducespulmonary hypertension. Circ Res2009,104(2):236-244,228p following244.
1Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT, Roedersheimer MT, van Rooijen N, StenmarkKR: Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of amonocyte/macrophage lineage. Am J Pathol2006,168(2):659-669.
2Barreiro O, Martin P, Gonzalez-Amaro R, Sanchez-Madrid F: Molecular cues guiding inflammatory responses.Cardiovasc Res2010,86(2):174-182.
3He P: Leucocyte/endothelium interactions and microvessel permeability: coupled or uncoupled? Cardiovasc Res2010,87(2):281-290.
4Winning S, Splettstoesser F, Fandrey J, Frede S: Acute hypoxia induces HIF-independent monocyte adhesion toendothelial cells through increased intercellular adhesion molecule-1expression: the role of hypoxic inhibition of prolylhydroxylase activity for the induction of NF-kappa B. J Immunol2010,185(3):1786-1793.
5Golembeski SM, West J, Tada Y, Fagan KA: Interleukin-6causes mild pulmonary hypertension and augmentshypoxia-induced pulmonary hypertension in mice. Chest2005,128(6Suppl):572S-573S.
6Csiszar A, Wang M, Lakatta EG, Ungvari Z: Inflammation and endothelial dysfunction during aging: role ofNF-kappaB. Journal of applied physiology (Bethesda, Md:1985)2008,105(4):1333-1341.
7Culver C, Sundqvist A, Mudie S, Melvin A, Xirodimas D, Rocha S: Mechanism of hypoxia-induced NF-kappaB. MolCell Biol2010,30(20):4901-4921.
8Tong Q, Zheng L, Lin L, Li B, Wang D, Li D: Hypoxia-induced mitogenic factor promotes vascular sion molecule-1expression via the PI-3K/Akt-NF-kappaB signaling pathway. Am J Respir Cell Mol Biol6,35(4):444-456.
1Hargreaves DC, Crabtree GR: ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res2011,21(3):396-420.
Schnitzler G, Sif S, Kingston RE: Human SWI/SNF interconverts a nucleosome between its base state and a stableremodeled state. Cell1998,94(1):17-27.
Takeuchi JK, Lou X, Alexander JM, Sugizaki H, Delgado-Olguin P, Holloway AK, Mori AD, Wylie JN, Munson C,Zhu Y et al: Chromatin remodelling complex dosage modulates transcription factor function in heart development. NatCommun2011,2:187.
Khavari PA, Peterson CL, Tamkun JW, Mendel DB, Crabtree GR: BRG1contains a conserved domain of theSWI2/SNF2family necessary for normal mitotic growth and transcription. Nature1993,366(6451):170-174.
Reyes JC, Barra J, Muchardt C, Camus A, Babinet C, Yaniv M: Altered control of cellular proliferation in the absencef mammalian brahma (SNF2alpha). EMBO J1998,17(23):6979-6991.
Rodriguez-Nieto S, Sanchez-Cespedes M: BRG1and LKB1: tales of two tumor suppressor genes on chromosome19pand lung cancer. Carcinogenesis2009,30(4):547-554.
Trotter KW, Archer TK: Nuclear receptors and chromatin remodeling machinery. Mol Cell Endocrinol2007,265-266:162-167.
Yoo AS, Crabtree GR: ATP-dependent chromatin remodeling in neural development. Curr Opin Neurobiol2009,19(2):120-126.
Saladi SV, Keenen B, Marathe HG, Qi H, Chin KV, de la Serna IL: Modulation of extracellular matrix/adhesionmolecule expression by BRG1is associated with increased melanoma invasiveness. Mol Cancer2010,9:280.
Zhang L, Zhang Q, Jones K, Patel M, Gong F: The chromatin remodeling factor BRG1stimulates nucleotide excisionrepair by facilitating recruitment of XPC to sites of DNA damage. Cell Cycle2009,8(23):3953-3959.
Dykhuizen EC, Hargreaves DC, Miller EL, Cui K, Korshunov A, Kool M, Pfister S, Cho YJ, Zhao K, Crabtree GR:BAF complexes facilitate decatenation of DNA by topoisomerase IIalpha. Nature2013,497(7451):624-627.
1Kadam S, Emerson BM: Transcriptional specificity of human SWI/SNF BRG1and BRM chromatin remodelingcomplexes. Mol Cell2003,11(2):377-389.
2Naito M, Zager RA, Bomsztyk K: BRG1increases transcription of proinflammatory genes in renal ischemia. J Am SocNephrol2009,20(8):1787-1796.
3Wang F, Zhang R, Beischlag TV, Muchardt C, Yaniv M, Hankinson O: Roles of Brahma and Brahma/SWI2-relatedgene1in hypoxic induction of the erythropoietin gene. J Biol Chem2004,279(45):46733-46741.
4Zhou J, Zhang M, Fang H, El-Mounayri O, Rodenberg JM, Imbalzano AN, Herring BP: The SWI/SNF chromatinremodeling complex regulates myocardin-induced smooth muscle-specific gene expression. Arterioscler Thromb VascBiol2009,29(6):921-928.
5Limpert AS, Bai S, Narayan M, Wu J, Yoon SO, Carter BD, Lu QR: NF-kappaB Forms a Complex with the ChromatinRemodeler BRG1to Regulate Schwann Cell Differentiation. J Neurosci2013,33(6):2388-2397.
6Zhang M, Fang H, Zhou J, Herring BP: A novel role of Brg1in the regulation of SRF/MRTFA-dependent smoothmuscle-specific gene expression. J Biol Chem2007,282(35):25708-25716.
7Sena JA, Wang L, Hu CJ. BRG1and BRM chromatin-remodeling complexes regulate the hypoxia response by actingas coactivators for a subset of hypoxia-inducible transcription factor target genes. Mol Cell Biol. Oct2013;33(19):3849-3863.
Fang F, Chen D, Yu L, Dai X, Yang Y, Tian W, Cheng X, Xu H, Weng X, Fang M et al: Proinflammatory stimuli engageBrahma related gene1and Brahma in endothelial injury. Circ Res2013,113(8):986-996.
1Mohrmann L, Verrijzer CP: Composition and functional specificity of SWI2/SNF2class chromatin remodelingcomplexes. Biochim Biophys Acta2005,1681(2-3):59-73.
2Trotter KW, Archer TK: The BRG1transcriptional coregulator. Nucl Recept Signal2008,6:e004.
Phelan ML, Sif S, Narlikar GJ, Kingston RE: Reconstitution of a core chromatin remodeling complex from SWI/SNFsubunits. Mol Cell1999,3(2):247-253.
1Hang CT, Yang J, Han P, Cheng HL, Shang C, Ashley E, Zhou B, Chang CP: Chromatin regulation by Brg1underliesheart muscle development and disease. Nature2010,466(7302):62-67.
Jiang C, Liu F, Luo Y, Li P, Chen J, Xu G, Wang Y, Li X, Huang J, Gao Y: Gene expression profiling of high altitudepolycythemia in Han Chinese migrating to the Qinghai-Tibetan plateau. Mol Med Rep2012,5(1):287-293.
Ariumi Y, Serhan F, Turelli P, Telenti A, Trono D: The integrase interactor1(INI1) proteins facilitate Tat-mediatedhuman immunodeficiency virus type1transcription. Retrovirology2006,3:47.
1Cao Y, Vo T, Millien G, Tagne JB, Kotton D, Mason RJ, Williams MC, Ramirez MI: Epigenetic mechanisms modulatethyroid transcription factor1-mediated transcription of the surfactant protein B gene. J Biol Chem2010,285(3):2152-2164.
2Coisy-Quivy M, Disson O, Roure V, Muchardt C, Blanchard JM, Dantonel JC: Role for Brm in cell growth control.Cancer Res2006,66(10):5069-5076.
3Zhang H, Gao Y, Zhao F, Dai Z, Meng T, Tu S, Yan Y: Hydrogen sulfide reduces mRNA and protein levels of beta-siteamyloid precursor protein cleaving enzyme1in PC12cells. Neurochem Int2011,58(2):169-175.
1高钰琪.高原军事医学.重庆：重庆出版社.2004
1Hou X, Chen J, Luo Y, Liu F, Xu G, Gao Y. Silencing of STIM1attenuates hypoxia-induced PASMCs proliferation viainhibition of the SOC/Ca2+/NFAT pathway. Respir Res.2013;14:2.
Phelan ML, Sif S, Narlikar GJ, Kingston RE: Reconstitution of a core chromatin remodeling complex from SWI/SNFsubunits. Mol Cell1999,3(2):247-253.
1Vachtenheim J, Ondrusova L, Borovansky J: SWI/SNF chromatin remodeling complex is critical for the expression ofmicrophthalmia-associated transcription factor in melanoma cells. Biochem Bioph Res Co2010,392(3):454-459.
2Miller SA, Mohn SE, Weinmann AS: Jmjd3and UTX play a demethylase-independent role in chromatin remodeling toregulate T-box family member-dependent gene expression. Mol Cell2010,40(4):594-605.
3Zhang HS, Gavin M, Dahiya A, Postigo AA, Ma D, Luo RX, Harbour JW, Dean DC: Exit from G1and S phase of thecell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell2000,101(1):79-89.
4Geiman TM, Sankpal UT, Robertson AK, Zhao Y, Zhao Y, Robertson KD: DNMT3B interacts with hSNF2H chromatinremodeling enzyme, HDACs1and2, and components of the histone methylation system. Biochem Biophys Res Commun2004,318(2):544-555.
5Sluiter W, Pietersma A, Lamers JM, Koster JF: Leukocyte adhesion molecules on the vascular endothelium: their rolein the pathogenesis of cardiovascular disease and the mechanisms underlying their expression. J Cardiovasc Pharmacol1993,22Suppl4:S37-44.
1de La Serna IL, Carlson KA, Hill DA, Guidi CJ, Stephenson RO, Sif S, Kingston RE, Imbalzano AN: MammalianSWI-SNF complexes contribute to activation of the hsp70gene. Mol Cell Biol2000,20(8):2839-2851.
2Voraberger G, Schafer R, Stratowa C: Cloning of the human gene for intercellular adhesion molecule1and analysis ofits5'-regulatory region. Induction by cytokines and phorbol ester. J Immunol1991,147(8):2777-2786.
3Munoz C, Castellanos MC, Alfranca A, Vara A, Esteban MA, Redondo JM, de Landazuri MO: Transcriptionalup-regulation of intracellular adhesion molecule-1in human endothelial cells by the antioxidant pyrrolidinedithiocarbamate involves the activation of activating protein-1. J Immunol1996,157(8):3587-3597.
Yu G, Rux AH, Ma P, Bdeir K, Sachais BS: Endothelial expression of E-selectin is induced by the platelet-specificchemokine platelet factor4through LRP in an NF-kappaB-dependent manner. Blood2005,105(9):3545-3551.
1Jeong KW, Lee YH, Stallcup MR: Recruitment of the SWI/SNF chromatin remodeling complex to steroidhormone-regulated promoters by nuclear receptor coactivator flightless-I. J Biol Chem2009,284(43):29298-29309.
2Treand C, du Chene I, Bres V, Kiernan R, Benarous R, Benkirane M, Emiliani S: Requirement for SWI/SNFchromatin-remodeling complex in Tat-mediated activation of the HIV-1promoter. EMBO J2006,25(8):1690-1699.
3Verma UN, Surabhi RM, Schmaltieg A, Becerra C, Gaynor RB: Small interfering RNAs directed against beta-catenininhibit the in vitro and in vivo growth of colon cancer cells. Clin Cancer Res2003,9(4):1291-1300.
1Bito T, Roy S, Sen CK, Shirakawa T, Gotoh A, Ueda M, Ichihashi M, Packer L: Flavonoids differentially regulate IFNgamma-induced ICAM-1expression in human keratinocytes: molecular mechanisms of action. FEBS Lett2002,520(1-3):145-152.
Hattori Y, Suzuki K, Hattori S, Kasai K: Metformin inhibits cytokine-induced nuclear factor kappaB activation viaAMP-activated protein kinase activation in vascular endothelial cells. Hypertension2006,47(6):1183-1188.
1Fang F, Yang Y, Yuan Z, Gao Y, Zhou J, Chen Q, Xu Y: Myocardin-Related Transcription Factor A MediatesOxLDL-Induced Endothelial Injury. Circ Res2011.
1Ritchie MH, Fillmore RA, Lausch RN, Oakes JE: A role for NF-kappa B binding motifs in the differential induction ofchemokine gene expression in human corneal epithelial cells. Invest Ophthalmol Vis Sci2004,45(7):2299-2305.
2Liu M, Kluger MS, D'Alessio A, Garcia-Cardena G, Pober JS: Regulation of arterial-venous differences in tumornecrosis factor responsiveness of endothelial cells by anatomic context. Am J Pathol2008,172(4):1088-1099.
1Winning S, Splettstoesser F, Fandrey J, Frede S: Acute hypoxia induces HIF-independent monocyte adhesion toendothelial cells through increased intercellular adhesion molecule-1expression: the role of hypoxic inhibition of prolylhydroxylase activity for the induction of NF-kappa B. J Immunol2010,185(3):1786-1793.
1Xu Y, Zhang J, Chen XB: The activity of p53is differentially regulated by Brm-and Brg1-containing SWI/SNFchromatin remodeling complexes. J Biol Chem2007,282(52):37429-37435.
2Reyes JC, Barra J, Muchardt C, Camus A, Babinet C, Yaniv M: Altered control of cellular proliferation in the absenceof mammalian brahma (SNF2alpha). EMBO J1998,17(23):6979-6991.
3Phelan ML, Sif S, Narlikar GJ, Kingston RE: Reconstitution of a core chromatin remodeling complex from SWI/SNFsubunits. Mol Cell1999,3(2):247-253.
4Halliday GM, Bock VL, Moloney FJ, Lyons JG: SWI/SNF: a chromatin-remodelling complex with a role incarcinogenesis. Int J Biochem Cell Biol2009,41(4):725-728.
5Monahan BJ, Villen J, Marguerat S, Bahler J, Gygi SP, Winston F: Fission yeast SWI/SNF and RSC complexes showcompositional and functional differences from budding yeast. Nat Struct Mol Biol2008,15(8):873-880.
1Zhang B, Chambers KJ, Faller DV, Wang S: Reprogramming of the SWI/SNF complex for co-activation orco-repression in prohibitin-mediated estrogen receptor regulation. Oncogene2007,26(50):7153-7157.
2Ramirez-Carrozzi VR, Nazarian AA, Li CC, Gore SL, Sridharan R, Imbalzano AN, Smale ST: Selective andantagonistic functions of SWI/SNF and Mi-2beta nucleosome remodeling complexes during an inflammatory response.Genes Dev2006,20(3):282-296.
3Naito M, Zager RA, Bomsztyk K: BRG1increases transcription of proinflammatory genes in renal ischemia. J Am SocNephrol2009,20(8):1787-1796.
4Angelov D, Lenouvel F, Hans F, Muller CW, Bouvet P, Bednar J, Moudrianakis EN, Cadet J, Dimitrov S: The histoneoctamer is invisible when NF-kappaB binds to the nucleosome. J Biol Chem2004,279(41):42374-42382.
1Jenuwein T, Allis CD: Translating the histone code. Science2001,293(5532):1074-1080.
1Langleben D: Endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Clin Chest Med2007,28(1):117-125, viii.
2Goerre S, Wenk M, Bartsch P, Luscher TF, Niroomand F, Hohenhaus E, Oelz O, Reinhart WH: Endothelin-1inpulmonary hypertension associated with high-altitude exposure. Circulation1995,91(2):359-364.
3Modesti PA, Vanni S, Morabito M, Modesti A, Marchetta M, Gamberi T, Sofi F, Savia G, Mancia G, Gensini GF et al:Role of endothelin-1in exposure to high altitude: Acute Mountain Sickness and Endothelin-1(ACME-1) study.Circulation2006,114(13):1410-1416.
Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ:Expression of endothelin-1in the lungs of patients with pulmonary hypertension. N Engl J Med1993,328(24):1732-1739.
5Yamashita K, Discher DJ, Hu J, Bishopric NH, Webster KA: Molecular regulation of the endothelin-1gene by hypoxia.Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP. J Biol Chem2001,276(16):12645-12653.
6Yang Y, Chen D, Yuan Z, et al. Megakaryocytic leukemia1(MKL1) ties the epigenetic machinery to hypoxia-inducedtransactivation of endothelin-1. Nucleic Acids Res. Jul12013;41(12):6005-6017.
Zhang M, Fang H, Zhou J, Herring BP: A novel role of Brg1in the regulation of SRF/MRTFA-dependent smoothmuscle-specific gene expression. J Biol Chem2007,282(35):25708-25716.
1Glenn DJ, Rahmutula D, Nishimoto M, Liang F, Gardner DG: Atrial natriuretic peptide suppresses endothelin geneexpression and proliferation in cardiac fibroblasts through a GATA4-dependent mechanism. Cardiovasc Res2009,84(2):209-217.
Vachtenheim J, Ondrusova L, Borovansky J: SWI/SNF chromatin remodeling complex is critical for the expression ofmicrophthalmia-associated transcription factor in melanoma cells. Biochem Bioph Res Co2010,392(3):454-459.
1Mawji IA, Robb GB, Tai SC, Marsden PA: Role of the3'-untranslated region of human endothelin-1in vascularendothelial cells. Contribution to transcript lability and the cellular heat shock response. J Biol Chem2004,279(10):8655-8667.
1Budhiraja R, Tuder RM, Hassoun PM: Endothelial dysfunction in pulmonary hypertension. Circulation2004,109(2):159-165.
2Yuan Z, Chen J, Chen D, Xu G, Xia M, Xu Y, Gao Y: Megakaryocytic Leukemia1(MKL1) Regulates Hypoxia InducedPulmonary Hypertension in Rats. PLoS One2014,9(3):e83895.
3Yang Y, Chen D, Yuan Z, et al. Megakaryocytic leukemia1(MKL1) ties the epigenetic machinery to hypoxia-inducedtransactivation of endothelin-1. Nucleic Acids Res. Jul12013;41(12):6005-6017.
4Zager RA, Johnson AC: Renal ischemia-reperfusion injury upregulates histone-modifying enzyme systems and altershistone expression at proinflammatory/profibrotic genes. Am J Physiol Renal Physiol2009,296(5): F1032-1041.
5Zhou J, Zhang M, Fang H, El-Mounayri O, Rodenberg JM, Imbalzano AN, Herring BP: The SWI/SNF chromatinremodeling complex regulates myocardin-induced smooth muscle-specific gene expression. Arterioscler Thromb VascBiol2009,29(6):921-928.
1Fang F, Chen D, Yu L, Dai X, Yang Y, Tian W, Cheng X, Xu H, Weng X, Fang M et al: Proinflammatory stimuli engageBrahma related gene1and Brahma in endothelial injury. Circ Res2013,113(8):986-996.
1Chen J, Tan B, Karteris E, Zervou S, Digby J, Hillhouse EW, Vatish M, Randeva HS: Secretion of adiponectin byhuman placenta: differential modulation of adiponectin and its receptors by cytokines. Diabetologia2006,49(6):1292-1302.
Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, Mirrakhimov MM, Aldashev A, Wilkins MR:Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation2001,104(4):424-428.
1Seldon MP, Silva G, Pejanovic N, Larsen R, Gregoire IP, Filipe J, Anrather J, Soares MP: Heme oxygenase-1inhibitsthe expression of adhesion molecules associated with endothelial cell activation via inhibition of NF-kappaB RelAphosphorylation at serine276. J Immunol2007,179(11):7840-7851.
2Ren G, Zhao X, Zhang L, Zhang J, L'Huillier A, Ling W, Roberts AI, Le AD, Shi S, Shao C et al: Inflammatorycytokine-induced intercellular adhesion molecule-1and vascular cell adhesion molecule-1in mesenchymal stem cells arecritical for immunosuppression. J Immunol2010,184(5):2321-2328.
3Winkler F, Koedel U, Kastenbauer S, Pfister HW: Differential expression of nitric oxide synthases in bacterialmeningitis: role of the inducible isoform for blood-brain barrier breakdown. The Journal of infectious diseases2001,183(12):1749-1759.
1Mushaben EM, Hershey GK, Pauciulo MW, Nichols WC, Le Cras TD. Chronic allergic inflammation causes vascularremodeling and pulmonary hypertension in BMPR2hypomorph and wild-type mice. PLoS One.2012;7(3):e32468.
Tabima DM, Hacker TA, Chesler NC: Measuring right ventricular function in the normal and hypertensive mousehearts using admittance-derived pressure-volume loops. Am J Physiol Heart Circ Physiol2010,299(6):H2069-2075.
1Tabima DM, Hacker TA, Chesler NC: Measuring right ventricular function in the normal and hypertensive mousehearts using admittance-derived pressure-volume loops. Am J Physiol Heart Circ Physiol2010,299(6):H2069-2075.
Zhang B, Shen M, Xu M, Liu LL, Luo Y, Xu DQ, Wang YX, Liu ML, Liu Y, Dong HY et al: Role of macrophage migrationinhibitory factor in the proliferation of smooth muscle cell in pulmonary hypertension. Mediators Inflamm2012,2012:840737.
Arnaud C, Beguin PC, Lantuejoul S, Pepin JL, Guillermet C, Pelli G, Burger F, Buatois V, Ribuot C, Baguet JP et al:The inflammatory preatherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5inhibition. Am J Respir Crit Care Med2011,184(6):724-731.
Weber C, Zernecke A, Libby P: The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons frommouse models. Nat Rev Immunol2008,8(10):802-815.
Hang CT, Yang J, Han P, Cheng HL, Shang C, Ashley E, Zhou B, Chang CP: Chromatin regulation by Brg1underliesheart muscle development and disease. Nature2010,466(7302):62-67.
Tian W, Xu H, Fang F, Chen Q, Xu Y, Shen A: Brahma-related gene1bridges epigenetic regulation of proinflammatorycytokine production to steatohepatitis in mice. Hepatology2013,58(2):576-588.
1Glaros S, Cirrincione GM, Palanca A, Metzger D, Reisman D: Targeted knockout of BRG1potentiates lung cancerdevelopment. Cancer Res2008,68(10):3689-3696.
Reisman D, Glaros S, Thompson EA: The SWI/SNF complex and cancer. Oncogene2009,28(14):1653-1668.
3Vachtenheim J, Ondrusova L, Borovansky J: SWI/SNF chromatin remodeling complex is critical for the expression ofmicrophthalmia-associated transcription factor in melanoma cells. Biochem Bioph Res Co2010,392(3):454-459.
Ross S, Cheung E, Petrakis TG, Howell M, Kraus WL, Hill CS: Smads orchestrate specific histone modifications andchromatin remodeling to activate transcription. EMBO J2006,25(19):4490-4502
1高钰琪.高原军事医学.重庆出版社.2004.
2Sakao S, Tatsumi K. Vascular remodeling in pulmonary arterial hypertension: multiple cancer-like pathways andpossible treatment modalities. Int J Cardiol. Feb172011;147(1):4-12.
3Jeffery TK, Wanstall JC. Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonaryhypertension. Pharmacol Ther. Oct2001;92(1):1-20.
Mowen K, Tang J, Zhu W, et al. Arginine methylation of STAT1modulates IFNalpha/beta-induced transcription. Cell.2001;104(5):731-741.
1高钰琪.高原军事医学.重庆出版社.2004.
Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J AmColl Cardiol. Jun302009;54(1Suppl):S10-19.
Van Hung T, Emoto N, Vignon-Zellweger N, et al. Inhibition of vascular endothelial growth factor receptor underhypoxia causes severe, human-like pulmonary arterial hypertension in mice: Potential roles of interleukin-6andendothelin. Life Sci. Jan82014.
Burke DL, Frid MG, Kunrath CL, et al. Sustained hypoxia promotes the development of a pulmonary artery-specificchronic inflammatory microenvironment. Am J Physiol Lung Cell Mol Physiol. Aug2009;297(2):L238-250.
Tuder RM, Voelkel NF. Pulmonary hypertension and inflammation. Journal of Laboratory and Clinical Medicine.1998;132(1):16-24.
Humbert M, Monti G, Brenot F, et al. Increased interleukin-1and interleukin-6serum concentrations in severe primarypulmonary hypertension. Am J Respir Crit Care Med. May1995;151(5):1628-1631.
Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6overexpression inducespulmonary hypertension. Circ Res. Jan302009;104(2):236-244,228p following244.
李尚师,李素芝,郑必海,宋娟,李红,曲涛.:快速进入高原者血清NO及白介素-1,6,8含量变化观察.:中国煤炭工业医学杂志2007;10(9)1055-1056.
Matsuda N, Hattori Y. Systemic inflammatory response syndrome (SIRS): molecular pathophysiology and gene therapy.J Pharmacol Sci. Jul2006;101(3):189-198.
Young KC, Hussein SM, Dadiz R, et al. Toll-like receptor4-deficient mice are resistant to chronic hypoxia-inducedpulmonary hypertension. Exp Lung Res. Mar2010;36(2):111-119.
1Quarck R, Nawrot T, Meyns B, Delcroix M. C-reactive protein: a new predictor of adverse outcome in pulmonaryarterial hypertension. J Am Coll Cardiol. Apr72009;53(14):1211-1218.
2Li J, Li JJ, He JG, Nan JL, Guo YL, Xiong CM. Atorvastatin decreases C-reactive protein-induced inflammatoryresponse in pulmonary artery smooth muscle cells by inhibiting nuclear factor-kappaB pathway. Cardiovasc Ther. Spring2010;28(1):8-14.
Girgis RE, Mozammel S, Champion HC, et al. Regression of chronic hypoxic pulmonary hypertension by simvastatin.Am J Physiol Lung Cell Mol Physiol. May2007;292(5):L1105-1110.
4Zhang B, Shen M, Xu M, et al. Role of macrophage migration inhibitory factor in the proliferation of smooth musclecell in pulmonary hypertension. Mediators Inflamm.2012;2012:840737.
5Zhang Y, Talwar A, Tsang D, et al. Macrophage migration inhibitory factor mediates hypoxia-induced pulmonaryhypertension. Mol Med.2012;18:215-223.
6Chen D, Fang F, Yang Y, et al. Brahma-related gene1(Brg1) epigenetically regulates CAM activation during hypoxicpulmonary hypertension. Cardiovasc Res. Dec12013;100(3):363-373.
Yuan Z, Chen J, Chen D, et al. Megakaryocytic Leukemia1(MKL1) Regulates Hypoxia Induced PulmonaryHypertension in Rats. PLoS One.2014;9(3):e83895.
1Thangjam GS, Dimitropoulou C, Joshi AD, et al. Novel Mechanism of Attenuation of LPS-Induced NF-kB Activationby the hsp90Inhibitor,17-AAG, in Human Lung Microvascular Endothelial Cells. Am J Respir Cell Mol Biol. Dec42013.
2Ohata Y, Ogata S, Nakanishi K, et al. Proteomic analysis of the lung in rats with hypobaric hypoxia-induced pulmonaryhypertension. Histol Histopathol. Jul2013;28(7):893-902.
3Janssen LJ. Isoprostanes and lung vascular pathology. Am J Respir Cell Mol Biol. Oct2008;39(4):383-389.
4Hopkins N, McLoughlin P. The structural basis of pulmonary hypertension in chronic lung disease: remodelling,rarefaction or angiogenesis? J Anat. Oct2002;201(4):335-348.
Sarada S, Himadri P, Mishra C, Geetali P, Ram MS, Ilavazhagan G. Role of oxidative stress and NFkB inhypoxia-induced pulmonary edema. Exp Biol Med (Maywood). Sep2008;233(9):1088-1098.
6Doughan AK, Harrison DG, Dikalov SI. Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction:linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res. Feb292008;102(4):488-496.
7Fike CD, Dikalova A, Slaughter JC, Kaplowitz MR, Zhang Y, Aschner JL. Reactive oxygen species-reducing strategiesimprove pulmonary arterial responses to nitric oxide in piglets with chronic hypoxia-induced pulmonary hypertension.Antioxid Redox Signal. May102013;18(14):1727-1738.
8Fike CD, Aschner JL, Kaplowitz MR, Zhang Y, Madden JA. Reactive oxygen species scavengers improvevoltage-gated K(+) channel function in pulmonary arteries of newborn pigs with progressive hypoxia-induced pulmonaryhypertension. Pulm Circ. Sep2013;3(3):551-563.
1Zhou G, Dada LA, Wu M, et al. Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrialROS and hypoxia-inducible factor1. Am J Physiol Lung Cell Mol Physiol. Dec2009;297(6):L1120-1130.
2Wei HL, Zhang CY, Jin HF, Tang CS, Du JB. Hydrogen sulfide regulates lung tissue-oxidized glutathione and totalantioxidant capacity in hypoxic pulmonary hypertensive rats. Acta Pharmacol Sin. Jun2008;29(6):670-679.
3Yang Y, Zhang BK, Liu D, et al. Sodium hydrosulfide prevents hypoxia-induced pulmonary arterial hypertension inbroilers. British poultry science.2012;53(5):608-615.
4Villegas LR, Kluck D, Field C, et al. Superoxide dismutase mimetic, MnTE-2-PyP, attenuates chronic hypoxia-inducedpulmonary hypertension, pulmonary vascular remodeling, and activation of the NALP3inflammasome. Antioxid RedoxSignal. May102013;18(14):1753-1764.
5Chandel NS, Trzyna WC, McClintock DS, Schumacker PT. Role of oxidants in NF-kappa B activation and TNF-alphagene transcription induced by hypoxia and endotoxin. J Immunol. Jul152000;165(2):1013-1021.
6Klinke A, Moller A, Pekarova M, et al. Protective Effects of10-Nitro-Oleic Acid in a Hypoxia-Induced Murine Modelof Pulmonary Hypertension. Am J Respir Cell Mol Biol. Feb122014.
7Zhang B, Niu W, Xu D, et al. Oxymatrine prevents hypoxia-and monocrotaline-induced pulmonary hypertension inrats. Free Radic Biol Med. Jan152014.
Dorfmuller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J. Aug2003;22(2):358-363.
1Burke DL, Frid MG, Kunrath CL, et al. Sustained hypoxia promotes the development of a pulmonary artery-specificchronic inflammatory microenvironment. Am J Physiol Lung Cell Mol Physiol. Aug2009;297(2):L238-250.
2Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation.2004;109(2):159-165.
Bagnato A, Rosano L. Epithelial-mesenchymal transition in ovarian cancer progression: a crucial role for theendothelin axis. Cells Tissues Organs.2007;185(1-3):85-94.
4Masaki T. Historical review: Endothelin. Trends Pharmacol Sci. Apr2004;25(4):219-224.
5Li H, Chen SJ, Chen YF, et al. Enhanced endothelin-1and endothelin receptor gene expression in chronic hypoxia.Journal of applied physiology (Bethesda, Md.:1985). Sep1994;77(3):1451-1459.
6Van Hung T, Emoto N, Vignon-Zellweger N, et al. Inhibition of vascular endothelial growth factor receptor underhypoxia causes severe, human-like pulmonary arterial hypertension in mice: Potential roles of interleukin-6and
7endothelin. Life Sci. Jan82014.Rubens C, Ewert R, Halank M, et al. Big endothelin-1and endothelin-1plasma levels are correlated with the severityof primary pulmonary hypertension. Chest. Nov2001;120(5):1562-1569.
8Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1in pulmonary hypertension: marker ormediator of disease? Ann Intern Med. Mar151991;114(6):464-469.
9Yang Y, Chen D, Yuan Z, et al. Megakaryocytic leukemia1(MKL1) ties the epigenetic machinery to hypoxia-inducedtransactivation of endothelin-1. Nucleic Acids Res. Jul12013;41(12):6005-6017.
10Jain R, Shaul PW, Borok Z, Willis BC. Endothelin-1induces alveolar epithelial-mesenchymal transition throughendothelin type A receptor-mediated production of TGF-beta1. Am J Respir Cell Mol Biol. Jul2007;37(1):38-47.
Rosano L, Spinella F, Di Castro V, et al. Endothelin-1promotes epithelial-to-mesenchymal transition in humanovarian cancer cells. Cancer Res. Dec152005;65(24):11649-11657.
1Dias-Junior CA, Cau SB, Tanus-Santos JE.[Role of nitric oxide in the control of the pulmonary circulation:physiological, pathophysiological, and therapeutic implications]. J Bras Pneumol. Jun2008;34(6):412-419.
2李尚师,李素芝,郑必海,宋娟,李红,曲涛.:快速进入高原者血清NO及白介素-1,6,8含量变化观察.:中国煤炭工业医学杂志2007;10(9)1055-1056.
3Naeije R, Dedobbeleer C. Pulmonary hypertension and the right ventricle in hypoxia. Exp Physiol. Aug2013;98(8):1247-1256.
Yuan Z, Chen J, Chen D, et al. Megakaryocytic Leukemia1(MKL1) Regulates Hypoxia Induced PulmonaryHypertension in Rats. PLoS One.2014;9(3):e83895.
5Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. Oct1999;79(4):1283-1316.
6Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res. Sep162005;97(6):512-523.
7韩雅玲,肖艳平,齐岩梅,康建,徐凯,闫承慧.:胚胎血管发育早期PDGF-BB对血管平滑肌细胞趋化的影响.:中国病理生理杂志2008;24(2)251-256.
8Ciuclan L, Hussey MJ, Burton V, et al. Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathologyvia reduction in5-hydroxytryptamine through inhibition of tryptophan hydroxylase1expression. Am J Respir Crit CareMed. Jan12013;187(1):78-89.
9Merklinger SL, Jones PL, Martinez EC, Rabinovitch M. Epidermal growth factor receptor blockade mediates smoothmuscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation. Jul192005;112(3):423-431.
10Tuder RM, Cool CD, Yeager M, Taraseviciene-Stewart L, Bull TM, Voelkel NF. The pathobiology of pulmonaryhypertension. Endothelium. Clin Chest Med. Sep2001;22(3):405-418.
11Tamm M, Bihl M, Eickelberg O, Stulz P, Perruchoud AP, Roth M. Hypoxia-induced interleukin-6and interleukin-8production is mediated by platelet-activating factor and platelet-derived growth factor in primary human lung cells. Am JRespir Cell Mol Biol. Oct1998;19(4):653-661.
1Teyssier C, Le Romancer M, Sentis S, Jalaguier S, Corbo L, Cavailles V. Protein arginine methylation in estrogensignaling and estrogen-related cancers. Trends Endocrinol Metab. Mar2010;21(3):181-189.
2Wilkins MR, Wharton J, Grimminger F, Ghofrani HA. Phosphodiesterase inhibitors for the treatment of pulmonaryhypertension. Eur Respir J. Jul2008;32(1):198-209.
3Rashid M, Fahim M, Kotwani A. Efficacy of tadalafil in chronic hypobaric hypoxia-induced pulmonary hypertension:possible mechanisms. Fundamental&clinical pharmacology. Jun2013;27(3):271-278.
4Tsai BM, Turrentine MW, Sheridan BC, et al. Differential effects of phosphodiesterase-5inhibitors on hypoxicpulmonary vasoconstriction and pulmonary artery cytokine expression. Ann Thorac Surg. Jan2006;81(1):272-278.
5Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane andprostacyclin metabolites in pulmonary hypertension. N Engl J Med. Jul91992;327(2):70-75.
6Takemiya K, Kai H, Yasukawa H, Tahara N, Kato S, Imaizumi T. Mesenchymal stem cell-based prostacyclin synthasegene therapy for pulmonary hypertension rats. Basic Res Cardiol. May2010;105(3):409-417.
7高钰琪.高原军事医学.重庆出版社.2004.
1Bonnet S, Archer SL. Potassium channel diversity in the pulmonary arteries and pulmonary veins: implications forregulation of the pulmonary vasculature in health and during pulmonary hypertension. Pharmacol Ther. Jul2007;115(1):56-69.
2Yuan JX, Aldinger AM, Juhaszova M, et al. Dysfunctional voltage-gated K+channels in pulmonary artery smoothmuscle cells of patients with primary pulmonary hypertension. Circulation. Oct61998;98(14):1400-1406.
3Dong L, Li Y, Hu H, et al. Potential therapeutic targets for hypoxia-induced pulmonary artery hypertension. J TranslMed. Feb82014;12(1):39.
Nitta CH, Osmond DA, Herbert LM, et al. Role of ASIC1in the development of chronic hypoxia-induced pulmonaryhypertension. Am J Physiol Heart Circ Physiol. Jan12014;306(1):H41-52.
1Cheever KH. An overview of pulmonary arterial hypertension: risks, pathogenesis, clinical manifestations, andmanagement. J Cardiovasc Nurs. Mar-Apr2005;20(2):108-116; quiz117-108.
2Crosswhite P, Sun Z. Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension. J Hypertens.Feb2010;28(2):201-212.
3Wang Y, Wysocka J, Sayegh J, et al. Human PAD4regulates histone arginine methylation levels via demethylimination.Science.2004;306(5694):279-283.
van Dijk TB, Gillemans N, Stein C, et al. Friend of Prmt1, a novel chromatin target of protein argininemethyltransferases. Mol Cell Biol. Jan2010;30(1):260-272.
5Huang X, Fan R, Lu Y, et al. Regulatory effect of AMP-activated protein kinase on pulmonary hypertension induced bychronic hypoxia in rats: in vivo and in vitro studies. Mol Biol Rep. Feb252014.
6Shimizu T, Fukumoto Y, Tanaka S, Satoh K, Ikeda S, Shimokawa H. Crucial role of ROCK2in vascular smooth musclecells for hypoxia-induced pulmonary hypertension in mice. Arterioscler Thromb Vasc Biol. Dec2013;33(12):2780-2791.
7Malczyk M, Veith C, Fuchs B, et al. Classical transient receptor potential channel1in hypoxia-induced pulmonaryhypertension. Am J Respir Crit Care Med. Dec152013;188(12):1451-1459.
Horita H, Furgeson SB, Ostriker A, et al. Selective inactivation of PTEN in smooth muscle cells synergizes withhypoxia to induce severe pulmonary hypertension. Journal of the American Heart Association. Jun2013;2(3):e000188.
1Horita H, Furgeson SB, Ostriker A, et al. Selective inactivation of PTEN in smooth muscle cells synergizes withhypoxia to induce severe pulmonary hypertension. Journal of the American Heart Association. Jun2013;2(3):e000188.
2Nie X, Shi Y, Yu W, Xu J, Hu X, Du Y. Phosphorylation of PTEN increase in pathological right ventricular hypertrophyin rats with chronic hypoxia induced pulmonary hypertension. Chin Med J (Engl).2014;127(2):338-342.
3x Yi ES, Kim H, Ahn H, et al. Distribution of obstructive intimal lesions and their cellular phenotypes in chronicpulmonary hypertension. A morphometric and immunohistochemical study. Am J Respir Crit Care Med. Oct2000;162(4Pt1):1577-1586.
4Frid MG, Brunetti JA, Burke DL, et al. Hypoxia-induced pulmonary vascular remodeling requires recruitment ofcirculating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol. Feb2006;168(2):659-669.
5Stenmark KR, Davie N, Frid M, Gerasimovskaya E, Das M. Role of the adventitia in pulmonary vascular remodeling.Physiology (Bethesda). Apr2006;21:134-145.
6Quinn AM, Bedford MT, Espejo A, et al. A homogeneous method for investigation of methylation-dependentprotein-protein interactions in epigenetics. Nucleic Acids Res. Jan2010;38(2):e11.
7Morrell NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am CollCardiol. Jun302009;54(1Suppl):S20-31.
8Li XW, Du J, Hu GY, et al. Fluorofenidone attenuates vascular remodeling in hypoxia-induced pulmonary hypertensionof rats. Can J Physiol Pharmacol. Jan2014;92(1):58-69.
9Goumans MJ, Liu Z, ten Dijke P. TGF-beta signaling in vascular biology and dysfunction. Cell Res. Jan2009;19(1):116-127.
10Zhu PC, Huang L, Ge XN, Yan F, Wu RL, Ao QL. Transdifferentiation of pulmonary arteriolar endothelial cells intosmooth muscle-like cells regulated by myocardin involved in hypoxia-induced pulmonary vascular remodelling.International Journal of Experimental Pathology. Dec2006;87(6):463-474.
11Carvajal G, Rodriguez-Vita J, Rodrigues-Diez R, et al. Angiotensin II activates the Smad pathway during epithelialmesenchymal transdifferentiation. Kidney Int. Sep2008;74(5):585-595.
Wolf G. Renal injury due to renin-angiotensin-aldosterone system activation of the transforming growth factor-betapathway. Kidney Int. Dec2006;70(11):1914-1919.
1High FA, Zhang M, Proweller A, et al. An essential role for Notch in neural crest during cardiovascular developmentand smooth muscle differentiation. J Clin Invest. Feb2007;117(2):353-363.
2Morrow D, Guha S, Sweeney C, et al. Notch and vascular smooth muscle cell phenotype. Circ Res. Dec52008;103(12):1370-1382.
3Doi H, Iso T, Sato H, et al. Jagged1-selective notch signaling induces smooth muscle differentiation via aRBP-Jkappa-dependent pathway. J Biol Chem. Sep292006;281(39):28555-28564.
4Noseda M, McLean G, Niessen K, et al. Notch activation results in phenotypic and functional changes consistent withendothelial-to-mesenchymal transformation. Circ Res. Apr162004;94(7):910-917.
5Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol. Apr2000;109(1):235-242.
6Silva GV, Litovsky S, Assad JA, et al. Mesenchymal stem cells differentiate into an endothelial phenotype, enhancevascular density, and improve heart function in a canine chronic ischemia model. Circulation. Jan182005;111(2):150-156.
7Nikolova-Krstevski V, Bhasin M, Otu HH, Libermann T, Oettgen P. Gene expression analysis of embryonic stem cellsexpressing VE-cadherin (CD144) during endothelial differentiation. BMC Genomics.2008;9:240.
8Abedin M, Tintut Y, Demer LL. Mesenchymal stem cells and the artery wall. Circ Res. Oct12004;95(7):671-676.
9Hamano K, Li TS.[Cell-based therapeutic angiogenesis for the treatment of ischemic disease]. Nippon Geka GakkaiZasshi. Aug2004;105(8):464-468.
10Fuchs S, Baffour R, Zhou YF, et al. Transendocardial delivery of autologous bone marrow enhances collateralperfusion and regional function in pigs with chronic experimental myocardial ischemia. J Am Coll Cardiol. May2001;37(6):1726-1732.
1Ball MK, Waypa GB, Mungai PT, et al. Regulation of Hypoxia-induced Pulmonary Hypertension by Vascular SmoothMuscle Hypoxia-Inducible Factor-1alpha. Am J Respir Crit Care Med. Feb12014;189(3):314-324.
2Yan J, Shen Y, Wang Y, Li BB. Increased expression of hypoxia-inducible factor-1alpha in proliferating neointimallesions in a rat model of pulmonary arterial hypertension. Am J Med Sci. Feb2013;345(2):121-128.
3Shan F, Li J, Huang QY. HIF-1Alpha-Induced Up-Regulation of miR-9Contributes to Phenotypic Modulation inPulmonary Artery Smooth Muscle Cells During Hypoxia. J Cell Physiol. Feb252014.
4Kim SY, Choi YJ, Joung SM, Lee BH, Jung YS, Lee JY. Hypoxic stress up-regulates the expression of Toll-likereceptor4in macrophages via hypoxia-inducible factor. Immunology. Apr2010;129(4):516-524.
Zimnicka AM, Tang H, Guo Q, et al. Upregulated copper transporters in hypoxia-induced pulmonary hypertension.PLoS One.2014;9(3):e90544.
6Yue J, Guan J, Wang X, et al. MicroRNA-206is involved in hypoxia-induced pulmonary hypertension throughtargeting of the HIF-1alpha/Fhl-1pathway. Lab Invest. Jul2013;93(7):748-759.
7Hansmann G, Wagner RA, Schellong S, et al. Pulmonary arterial hypertension is linked to insulin resistance andreversed by peroxisome proliferator-activated receptor-gamma activation. Circulation. Mar132007;115(10):1275-1284.
8Rabinovitch M. PPARgamma and the pathobiology of pulmonary arterial hypertension. Adv Exp Med Biol.2010;661:447-458.
Li M, Li Z, Sun X, et al. Heme oxygenase-1/p21WAF1mediates peroxisome proliferator-activated receptor-gammasignaling inhibition of proliferation of rat pulmonary artery smooth muscle cells. FEBS J. Mar2010;277(6):1543-1550.
[1]高钰琪.高原军事医学.重庆：重庆出版社.2004
[2] Yidiz P. Molecular mechanisms of pulmonary hypertension. Clinica Chimica Acta.May2009;403(1-2):9-16.
[3] Ward JP, McMurtry IF. Mechanisms of hypoxic pulmonary vasoconstriction andtheir roles in pulmonary hypertension: new findings for an old problem. Curr OpinPharmacol. Jun2009;9(3):287-296.
[4] Rabinovitch M, Bothwell T, Hayakawa BN, Williams WG, Trusler GA, Rowe RD,Olley PM, Cutz E: Pulmonary artery endothelial abnormalities in patients withcongenital heart defects and pulmonary hypertension. A correlation of light withscanning electron microscopy and transmission electron microscopy. Lab Invest1986,55(6):632-653.
[5]陈小容,邹霞英:缺氧性肺动脉高压大鼠肺血管内皮细胞的变化.中国病理生理杂志1996,12(6):608-611.
[6] Botto L, Beretta E, Daffara R, Miserocchi G, Palestini P: Biochemical andmorphological changes in endothelial cells in response to hypoxic interstitial edema.Respir Res2006,7:7.
[7] Bagnato A, Rosano L. Epithelial-mesenchymal transition in ovarian cancerprogression: a crucial role for the endothelin axis. Cells Tissues Organs.2007;185(1-3):85-94.
[8] Li H, Chen SJ, Chen YF, et al. Enhanced endothelin-1and endothelin receptor geneexpression in chronic hypoxia. Journal of applied physiology (Bethesda, Md.:1985).Sep1994;77(3):1451-1459.
[9] Rubens C, Ewert R, Halank M, et al. Big endothelin-1and endothelin-1plasmalevels are correlated with the severity of primary pulmonary hypertension. Chest.Nov2001;120(5):1562-1569.
[10] Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1inpulmonary hypertension: marker or mediator of disease? Ann Intern Med. Mar151991;114(6):464-469.
[11] Yamashita K, Discher DJ, Hu J, Bishopric NH, Webster KA: Molecular regulation ofthe endothelin-1gene by hypoxia. Contributions of hypoxia-inducible factor-1,activator protein-1, GATA-2, AND p300/CBP. J Biol Chem2001,276(16):12645-12653.
[12] Yang Y, Chen D, Yuan Z, et al. Megakaryocytic leukemia1(MKL1) ties theepigenetic machinery to hypoxia-induced transactivation of endothelin-1. NucleicAcids Res. Jul12013;41(12):6005-6017.
[13] Savale L, Tu L, Rideau D, Izziki M, Maitre B, Adnot S, Eddahibi S: Impact ofinterleukin-6on hypoxia-induced pulmonary hypertension and lung inflammation inmice. Respir Res2009,10:6.
[14] Burke DL, Frid MG, Kunrath CL, Karoor V, Anwar A, Wagner BD, Strassheim D,Stenmark KR: Sustained hypoxia promotes the development of a pulmonaryartery-specific chronic inflammatory microenvironment. Am J Physiol Lung CellMol Physiol2009,297(2):L238-250.
[15] Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB:Interleukin-6overexpression induces pulmonary hypertension. Circ Res2009,104(2):236-244,228p following244.
[16] Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT,Roedersheimer MT, van Rooijen N, Stenmark KR: Hypoxia-induced pulmonaryvascular remodeling requires recruitment of circulating mesenchymal precursors of amonocyte/macrophage lineage. Am J Pathol2006,168(2):659-669.
[17] Barreiro O, Martin P, Gonzalez-Amaro R, Sanchez-Madrid F: Molecular cuesguiding inflammatory responses. Cardiovasc Res2010,86(2):174-182.
[18] He P: Leucocyte/endothelium interactions and microvessel permeability: coupled oruncoupled? Cardiovasc Res2010,87(2):281-290.
[19] Winning S, Splettstoesser F, Fandrey J, Frede S: Acute hypoxia inducesHIF-independent monocyte adhesion to endothelial cells through increasedintercellular adhesion molecule-1expression: the role of hypoxic inhibition of prolylhydroxylase activity for the induction of NF-kappa B. J Immunol2010,185(3):1786-1793.
[20] Golembeski SM, West J, Tada Y, Fagan KA: Interleukin-6causes mild pulmonaryhypertension and augments hypoxia-induced pulmonary hypertension in mice. Chest2005,128(6Suppl):572S-573S.
[21] Csiszar A, Wang M, Lakatta EG, Ungvari Z: Inflammation and endothelialdysfunction during aging: role of NF-kappaB. Journal of applied physiology(Bethesda, Md:1985)2008,105(4):1333-1341.
[22] Culver C, Sundqvist A, Mudie S, Melvin A, Xirodimas D, Rocha S: Mechanism ofhypoxia-induced NF-kappaB. Mol Cell Biol2010,30(20):4901-4921.
[23] Tong Q, Zheng L, Lin L, Li B, Wang D, Li D: Hypoxia-induced mitogenic factorpromotes vascular sion molecule-1expression via the PI-3K/Akt-NF-kappaBsignaling pathway. Am J Respir Cell Mol Biol6,35(4):444-456.
[24] Hargreaves DC, Crabtree GR: ATP-dependent chromatin remodeling: genetics,genomics and mechanisms. Cell Res2011,21(3):396-420.
[25] Schnitzler G, Sif S, Kingston RE: Human SWI/SNF interconverts a nucleosomebetween its base state and a stable remodeled state. Cell1998,94(1):17-27.
[26] Takeuchi JK, Lou X, Alexander JM, Sugizaki H, Delgado-Olguin P, Holloway AK,Mori AD, Wylie JN, Munson C, Zhu Y et al: Chromatin remodelling complexdosage modulates transcription factor function in heart development. Nat Commun2011,2:187.
[27] Khavari PA, Peterson CL, Tamkun JW, Mendel DB, Crabtree GR: BRG1contains aconserved domain of the SWI2/SNF2family necessary for normal mitotic growthand transcription. Nature1993,366(6451):170-174.
[28] Reyes JC, Barra J, Muchardt C, Camus A, Babinet C, Yaniv M: Altered control ofcellular proliferation in the absence of mammalian brahma (SNF2alpha). EMBO J1998,17(23):6979-6991.
[29] Rodriguez-Nieto S, Sanchez-Cespedes M: BRG1and LKB1: tales of two tumorsuppressor genes on chromosome19p and lung cancer. Carcinogenesis2009,30(4):547-554.
[30] Trotter KW, Archer TK: Nuclear receptors and chromatin remodeling machinery.Mol Cell Endocrinol2007,265-266:162-167.
[31] Yoo AS, Crabtree GR: ATP-dependent chromatin remodeling in neural development.Curr Opin Neurobiol2009,19(2):120-126.
[32] Saladi SV, Keenen B, Marathe HG, Qi H, Chin KV, de la Serna IL: Modulation ofextracellular matrix/adhesion molecule expression by BRG1is associated withincreased melanoma invasiveness. Mol Cancer2010,9:280.
[33] Zhang L, Zhang Q, Jones K, Patel M, Gong F: The chromatin remodeling factorBRG1stimulates nucleotide excision repair by facilitating recruitment of XPC tosites of DNA damage. Cell Cycle2009,8(23):3953-3959.
[34] Dykhuizen EC, Hargreaves DC, Miller EL, Cui K, Korshunov A, Kool M, Pfister S,Cho YJ, Zhao K, Crabtree GR: BAF complexes facilitate decatenation of DNA bytopoisomerase IIalpha. Nature2013,497(7451):624-627.
[35] Kadam S, Emerson BM: Transcriptional specificity of human SWI/SNF BRG1andBRM chromatin remodeling complexes. Mol Cell2003,11(2):377-389.
[36] Naito M, Zager RA, Bomsztyk K: BRG1increases transcription of proinflammatorygenes in renal ischemia. J Am Soc Nephrol2009,20(8):1787-1796.
[37] Wang F, Zhang R, Beischlag TV, Muchardt C, Yaniv M, Hankinson O: Roles ofBrahma and Brahma/SWI2-related gene1in hypoxic induction of the erythropoietingene. J Biol Chem2004,279(45):46733-46741.
[38] Zhou J, Zhang M, Fang H, El-Mounayri O, Rodenberg JM, Imbalzano AN, HerringBP: The SWI/SNF chromatin remodeling complex regulates myocardin-inducedsmooth muscle-specific gene expression. Arterioscler Thromb Vasc Biol2009,29(6):921-928.
[39] Limpert AS, Bai S, Narayan M, Wu J, Yoon SO, Carter BD, Lu QR: NF-kappaBForms a Complex with the Chromatin Remodeler BRG1to Regulate Schwann CellDifferentiation. J Neurosci2013,33(6):2388-2397.
[40] Zhang M, Fang H, Zhou J, Herring BP: A novel role of Brg1in the regulation ofSRF/MRTFA-dependent smooth muscle-specific gene expression. J Biol Chem2007,282(35):25708-25716.
[41] Sena JA, Wang L, Hu CJ. BRG1and BRM chromatin-remodeling complexesregulate the hypoxia response by acting as coactivators for a subset ofhypoxia-inducible transcription factor target genes. Mol Cell Biol. Oct2013;33(19):3849-3863.
[42] Fang F, Chen D, Yu L, Dai X, Yang Y, Tian W, Cheng X, Xu H, Weng X, Fang M etal: Proinflammatory stimuli engage Brahma related gene1and Brahma inendothelial injury. Circ Res2013,113(8):986-996.
[43] Mohrmann L, Verrijzer CP: Composition and functional specificity of SWI2/SNF2class chromatin remodeling complexes. Biochim Biophys Acta2005,1681(2-3):59-73.
[44] Trotter KW, Archer TK: The BRG1transcriptional coregulator. Nucl Recept Signal2008,6:e004.
[45] Phelan ML, Sif S, Narlikar GJ, Kingston RE: Reconstitution of a core chromatinremodeling complex from SWI/SNF subunits. Mol Cell1999,3(2):247-253.
[46] Hang CT, Yang J, Han P, Cheng HL, Shang C, Ashley E, Zhou B, Chang CP:Chromatin regulation by Brg1underlies heart muscle development and disease.Nature2010,466(7302):62-67.
[47] Jiang C, Liu F, Luo Y, Li P, Chen J, Xu G, Wang Y, Li X, Huang J, Gao Y: Geneexpression profiling of high altitude polycythemia in Han Chinese migrating to theQinghai-Tibetan plateau. Mol Med Rep2012,5(1):287-293.
[48] Ariumi Y, Serhan F, Turelli P, Telenti A, Trono D: The integrase interactor1(INI1)proteins facilitate Tat-mediated human immunodeficiency virus type1transcription.Retrovirology2006,3:47.
[49] Cao Y, Vo T, Millien G, Tagne JB, Kotton D, Mason RJ, Williams MC, Ramirez MI:Epigenetic mechanisms modulate thyroid transcription factor1-mediatedtranscription of the surfactant protein B gene. J Biol Chem2010,285(3):2152-2164.
[50] Coisy-Quivy M, Disson O, Roure V, Muchardt C, Blanchard JM, Dantonel JC: Rolefor Brm in cell growth control. Cancer Res2006,66(10):5069-5076.
[51] Zhang H, Gao Y, Zhao F, Dai Z, Meng T, Tu S, Yan Y: Hydrogen sulfide reducesmRNA and protein levels of beta-site amyloid precursor protein cleaving enzyme1in PC12cells. Neurochem Int2011,58(2):169-175.
[52] Hou X, Chen J, Luo Y, Liu F, Xu G, Gao Y. Silencing of STIM1attenuateshypoxia-induced PASMCs proliferation via inhibition of the SOC/Ca2+/NFATpathway. Respir Res.2013;14:2.
[53] Vachtenheim J, Ondrusova L, Borovansky J: SWI/SNF chromatin remodelingcomplex is critical for the expression of microphthalmia-associated transcriptionfactor in melanoma cells. Biochem Bioph Res Co2010,392(3):454-459.
[54] Miller SA, Mohn SE, Weinmann AS: Jmjd3and UTX play a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression. Mol Cell2010,40(4):594-605.
[55] Zhang HS, Gavin M, Dahiya A, Postigo AA, Ma D, Luo RX, Harbour JW, Dean DC:Exit from G1and S phase of the cell cycle is regulated by repressor complexescontaining HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell2000,101(1):79-89.
[56] Geiman TM, Sankpal UT, Robertson AK, Zhao Y, Zhao Y, Robertson KD: DNMT3Binteracts with hSNF2H chromatin remodeling enzyme, HDACs1and2, andcomponents of the histone methylation system. Biochem Biophys Res Commun2004,318(2):544-555.
[57] Sluiter W, Pietersma A, Lamers JM, Koster JF: Leukocyte adhesion molecules on thevascular endothelium: their role in the pathogenesis of cardiovascular disease and themechanisms underlying their expression. J Cardiovasc Pharmacol1993,22Suppl4:S37-44.
[58] de La Serna IL, Carlson KA, Hill DA, Guidi CJ, Stephenson RO, Sif S, Kingston RE,Imbalzano AN: Mammalian SWI-SNF complexes contribute to activation of thehsp70gene. Mol Cell Biol2000,20(8):2839-2851.
[59] Voraberger G, Schafer R, Stratowa C: Cloning of the human gene for intercellularadhesion molecule1and analysis of its5'-regulatory region. Induction by cytokinesand phorbol ester. J Immunol1991,147(8):2777-2786.
[60] Munoz C, Castellanos MC, Alfranca A, Vara A, Esteban MA, Redondo JM, deLandazuri MO: Transcriptional up-regulation of intracellular adhesion molecule-1inhuman endothelial cells by the antioxidant pyrrolidine dithiocarbamate involves theactivation of activating protein-1. J Immunol1996,157(8):3587-3597.
[61] Yu G, Rux AH, Ma P, Bdeir K, Sachais BS: Endothelial expression of E-selectin isinduced by the platelet-specific chemokine platelet factor4through LRP in anNF-kappaB-dependent manner. Blood2005,105(9):3545-3551.
[62] Jeong KW, Lee YH, Stallcup MR: Recruitment of the SWI/SNF chromatinremodeling complex to steroid hormone-regulated promoters by nuclear receptorcoactivator flightless-I. J Biol Chem2009,284(43):29298-29309.
[63] Treand C, du Chene I, Bres V, Kiernan R, Benarous R, Benkirane M, Emiliani S:Requirement for SWI/SNF chromatin-remodeling complex in Tat-mediatedactivation of the HIV-1promoter. EMBO J2006,25(8):1690-1699.
[64] Verma UN, Surabhi RM, Schmaltieg A, Becerra C, Gaynor RB: Small interferingRNAs directed against beta-catenin inhibit the in vitro and in vivo growth of coloncancer cells. Clin Cancer Res2003,9(4):1291-1300.
[65] Bito T, Roy S, Sen CK, Shirakawa T, Gotoh A, Ueda M, Ichihashi M, Packer L:Flavonoids differentially regulate IFN gamma-induced ICAM-1expression in humankeratinocytes: molecular mechanisms of action. FEBS Lett2002,520(1-3):145-152.
[66] Hattori Y, Suzuki K, Hattori S, Kasai K: Metformin inhibits cytokine-inducednuclear factor kappaB activation via AMP-activated protein kinase activation invascular endothelial cells. Hypertension2006,47(6):1183-1188.
[67] Fang F, Yang Y, Yuan Z, Gao Y, Zhou J, Chen Q, Xu Y: Myocardin-RelatedTranscription Factor A Mediates OxLDL-Induced Endothelial Injury. Circ Res2011.
[68] Ritchie MH, Fillmore RA, Lausch RN, Oakes JE: A role for NF-kappa B bindingmotifs in the differential induction of chemokine gene expression in human cornealepithelial cells. Invest Ophthalmol Vis Sci2004,45(7):2299-2305.
[69] Liu M, Kluger MS, D'Alessio A, Garcia-Cardena G, Pober JS: Regulation ofarterial-venous differences in tumor necrosis factor responsiveness of endothelialcells by anatomic context. Am J Pathol2008,172(4):1088-1099.
[70] Xu Y, Zhang J, Chen XB: The activity of p53is differentially regulated by Brm-andBrg1-containing SWI/SNF chromatin remodeling complexes. J Biol Chem2007,282(52):37429-37435.
[71] Halliday GM, Bock VL, Moloney FJ, Lyons JG: SWI/SNF: a chromatin-remodellingcomplex with a role in carcinogenesis. Int J Biochem Cell Biol2009,41(4):725-728.
[72] Monahan BJ, Villen J, Marguerat S, Bahler J, Gygi SP, Winston F: Fission yeastSWI/SNF and RSC complexes show compositional and functional differences frombudding yeast. Nat Struct Mol Biol2008,15(8):873-880.
[73] Zhang B, Chambers KJ, Faller DV, Wang S: Reprogramming of the SWI/SNFcomplex for co-activation or co-repression in prohibitin-mediated estrogen receptorregulation. Oncogene2007,26(50):7153-7157.
[74] Ramirez-Carrozzi VR, Nazarian AA, Li CC, Gore SL, Sridharan R, Imbalzano AN,Smale ST: Selective and antagonistic functions of SWI/SNF and Mi-2betanucleosome remodeling complexes during an inflammatory response. Genes Dev2006,20(3):282-296.
[75] Angelov D, Lenouvel F, Hans F, Muller CW, Bouvet P, Bednar J, Moudrianakis EN,Cadet J, Dimitrov S: The histone octamer is invisible when NF-kappaB binds to thenucleosome. J Biol Chem2004,279(41):42374-42382.
[76] Jenuwein T, Allis CD: Translating the histone code. Science2001,293(5532):1074-1080.
[77] Langleben D: Endothelin receptor antagonists in the treatment of pulmonary arterialhypertension. Clin Chest Med2007,28(1):117-125, viii.
[78] Goerre S, Wenk M, Bartsch P, Luscher TF, Niroomand F, Hohenhaus E, Oelz O,Reinhart WH: Endothelin-1in pulmonary hypertension associated with high-altitudeexposure. Circulation1995,91(2):359-364.
[79] Modesti PA, Vanni S, Morabito M, Modesti A, Marchetta M, Gamberi T, Sofi F,Savia G, Mancia G, Gensini GF et al: Role of endothelin-1in exposure to highaltitude: Acute Mountain Sickness and Endothelin-1(ACME-1) study. Circulation2006,114(13):1410-1416.
[80] Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S,Masaki T, Duguid WP, Stewart DJ: Expression of endothelin-1in the lungs ofpatients with pulmonary hypertension. N Engl J Med1993,328(24):1732-1739.
[81] Glenn DJ, Rahmutula D, Nishimoto M, Liang F, Gardner DG: Atrial natriureticpeptide suppresses endothelin gene expression and proliferation in cardiacfibroblasts through a GATA4-dependent mechanism. Cardiovasc Res2009,84(2):209-217.
[82] Mawji IA, Robb GB, Tai SC, Marsden PA: Role of the3'-untranslated region ofhuman endothelin-1in vascular endothelial cells. Contribution to transcript labilityand the cellular heat shock response. J Biol Chem2004,279(10):8655-8667.
[83] Budhiraja R, Tuder RM, Hassoun PM: Endothelial dysfunction in pulmonaryhypertension. Circulation2004,109(2):159-165.
[84] Yuan Z, Chen J, Chen D, Xu G, Xia M, Xu Y, Gao Y: Megakaryocytic Leukemia1(MKL1) Regulates Hypoxia Induced Pulmonary Hypertension in Rats. PLoS One2014,9(3):e83895.
[85] Zager RA, Johnson AC: Renal ischemia-reperfusion injury upregulates histone-modifying enzyme systems and alters histone expression at proinflammatory/profibrotic genes. Am J Physiol Renal Physiol2009,296(5): F1032-1041.
[86] Chen J, Tan B, Karteris E, Zervou S, Digby J, Hillhouse EW, Vatish M, Randeva HS:Secretion of adiponectin by human placenta: differential modulation of adiponectinand its receptors by cytokines. Diabetologia2006,49(6):1292-1302.
[87] Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A,Mirrakhimov MM, Aldashev A, Wilkins MR: Sildenafil inhibits hypoxia-inducedpulmonary hypertension. Circulation2001,104(4):424-428.
[88] Seldon MP, Silva G, Pejanovic N, Larsen R, Gregoire IP, Filipe J, Anrather J, SoaresMP: Heme oxygenase-1inhibits the expression of adhesion molecules associatedwith endothelial cell activation via inhibition of NF-kappaB RelA phosphorylation atserine276. J Immunol2007,179(11):7840-7851.
[89] Ren G, Zhao X, Zhang L, Zhang J, L'Huillier A, Ling W, Roberts AI, Le AD, Shi S,Shao C et al: Inflammatory cytokine-induced intercellular adhesion molecule-1andvascular cell adhesion molecule-1in mesenchymal stem cells are critical forimmunosuppression. J Immunol2010,184(5):2321-2328.
[90] Winkler F, Koedel U, Kastenbauer S, Pfister HW: Differential expression of nitricoxide synthases in bacterial meningitis: role of the inducible isoform for blood-brainbarrier breakdown. The Journal of infectious diseases2001,183(12):1749-1759.
[91] Mushaben EM, Hershey GK, Pauciulo MW, Nichols WC, Le Cras TD. Chronicallergic inflammation causes vascular remodeling and pulmonary hypertension inBMPR2hypomorph and wild-type mice. PLoS One.2012;7(3):e32468.
[92] Tabima DM, Hacker TA, Chesler NC: Measuring right ventricular function in thenormal and hypertensive mouse hearts using admittance-derived pressure-volumeloops. Am J Physiol Heart Circ Physiol2010,299(6):H2069-2075.
[93] Stenmark KR, Bouchey D, Nemenoff R, Dempsey EC, Das M: Hypoxia-inducedpulmonary vascular remodeling: contribution of the adventitial fibroblasts. PhysiolRes2000,49(5):503-517.
[94] Zhang B, Shen M, Xu M, Liu LL, Luo Y, Xu DQ, Wang YX, Liu ML, Liu Y, DongHY et al: Role of macrophage migration inhibitory factor in the proliferation ofsmooth muscle cell in pulmonary hypertension. Mediators Inflamm2012,2012:840737.
[95] Arnaud C, Beguin PC, Lantuejoul S, Pepin JL, Guillermet C, Pelli G, Burger F,Buatois V, Ribuot C, Baguet JP et al: The inflammatory preatheroscleroticremodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5inhibition. Am J Respir Crit Care Med2011,184(6):724-731.
[96] Weber C, Zernecke A, Libby P: The multifaceted contributions of leukocyte subsetsto atherosclerosis: lessons from mouse models. Nat Rev Immunol2008,8(10):802-815.
[97] Tian W, Xu H, Fang F, Chen Q, Xu Y, Shen A: Brahma-related gene1bridgesepigenetic regulation of proinflammatory cytokine production to steatohepatitis inmice. Hepatology2013,58(2):576-588.
[98] Glaros S, Cirrincione GM, Palanca A, Metzger D, Reisman D: Targeted knockout ofBRG1potentiates lung cancer development. Cancer Res2008,68(10):3689-3696.
[99] Reisman D, Glaros S, Thompson EA: The SWI/SNF complex and cancer. Oncogene2009,28(14):1653-1668.
[100] Ross S, Cheung E, Petrakis TG, Howell M, Kraus WL, Hill CS: Smads orchestratespecific histone modifications and chromatin remodeling to activate transcription.EMBO J2006,25(19):4490-4502
[1]高钰琪.高原军事医学.重庆出版社.2004.
[2] Sakao S, Tatsumi K. Vascular remodeling in pulmonary arterial hypertension:multiple cancer-like pathways and possible treatment modalities. Int J Cardiol. Feb172011;147(1):4-12.
[3] Jeffery TK, Wanstall JC. Pulmonary vascular remodeling: a target for therapeuticintervention in pulmonary hypertension. Pharmacol Ther. Oct2001;92(1):1-20.
[4] Mowen K, Tang J, Zhu W, et al. Arginine methylation of STAT1modulatesIFNalpha/beta-induced transcription. Cell.2001;104(5):731-741.
[5] Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growth factors, andpulmonary vascular remodeling. J Am Coll Cardiol. Jun302009;54(1Suppl):S10-19.
[6] Van Hung T, Emoto N, Vignon-Zellweger N, et al. Inhibition of vascular endothelialgrowth factor receptor under hypoxia causes severe, human-like pulmonary arterialhypertension in mice: Potential roles of interleukin-6and endothelin. Life Sci. Jan82014.
[7] Burke DL, Frid MG, Kunrath CL, et al. Sustained hypoxia promotes thedevelopment of a pulmonary artery-specific chronic inflammatorymicroenvironment. Am J Physiol Lung Cell Mol Physiol. Aug2009;297(2):L238-250.
[8] Tuder RM, Voelkel NF. Pulmonary hypertension and inflammation. Journal ofLaboratory and Clinical Medicine.1998;132(1):16-24.
[9] Humbert M, Monti G, Brenot F, et al. Increased interleukin-1and interleukin-6serum concentrations in severe primary pulmonary hypertension. Am J Respir CritCare Med. May1995;151(5):1628-1631.
[10] Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB.Interleukin-6overexpression induces pulmonary hypertension. Circ Res. Jan302009;104(2):236-244,228p following244.
[11]李尚师,李素芝,郑必海,宋娟,李红,曲涛.:快速进入高原者血清NO及白介素-1,6,8含量变化观察.:中国煤炭工业医学杂志2007;10(9)1055-1056.
[12] Matsuda N, Hattori Y. Systemic inflammatory response syndrome (SIRS): molecularpathophysiology and gene therapy. J Pharmacol Sci. Jul2006;101(3):189-198.
[13] Young KC, Hussein SM, Dadiz R, et al. Toll-like receptor4-deficient mice areresistant to chronic hypoxia-induced pulmonary hypertension. Exp Lung Res. Mar2010;36(2):111-119.
[14] Quarck R, Nawrot T, Meyns B, Delcroix M. C-reactive protein: a new predictor ofadverse outcome in pulmonary arterial hypertension. J Am Coll Cardiol. Apr72009;53(14):1211-1218.
[15] Li J, Li JJ, He JG, Nan JL, Guo YL, Xiong CM. Atorvastatin decreases C-reactiveprotein-induced inflammatory response in pulmonary artery smooth muscle cells byinhibiting nuclear factor-kappaB pathway. Cardiovasc Ther. Spring2010;28(1):8-14.
[16] Girgis RE, Mozammel S, Champion HC, et al. Regression of chronic hypoxicpulmonary hypertension by simvastatin. Am J Physiol Lung Cell Mol Physiol. May2007;292(5):L1105-1110.
[17] Zhang B, Shen M, Xu M, et al. Role of macrophage migration inhibitory factor inthe proliferation of smooth muscle cell in pulmonary hypertension. MediatorsInflamm.2012;2012:840737.
[18] Zhang Y, Talwar A, Tsang D, et al. Macrophage migration inhibitory factor mediateshypoxia-induced pulmonary hypertension. Mol Med.2012;18:215-223.
[19] Chen D, Fang F, Yang Y, et al. Brahma-related gene1(Brg1) epigeneticallyregulates CAM activation during hypoxic pulmonary hypertension. Cardiovasc Res.Dec12013;100(3):363-373.
[20] Yuan Z, Chen J, Chen D, et al. Megakaryocytic Leukemia1(MKL1) RegulatesHypoxia Induced Pulmonary Hypertension in Rats. PLoS One.2014;9(3):e83895.
[21] Thangjam GS, Dimitropoulou C, Joshi AD, et al. Novel Mechanism of Attenuationof LPS-Induced NF-kB Activation by the hsp90Inhibitor,17-AAG, in Human LungMicrovascular Endothelial Cells. Am J Respir Cell Mol Biol. Dec42013.
[22] Ohata Y, Ogata S, Nakanishi K, et al. Proteomic analysis of the lung in rats withhypobaric hypoxia-induced pulmonary hypertension. Histol Histopathol. Jul2013;28(7):893-902.
[23] Janssen LJ. Isoprostanes and lung vascular pathology. Am J Respir Cell Mol Biol.Oct2008;39(4):383-389.
[24] Hopkins N, McLoughlin P. The structural basis of pulmonary hypertension inchronic lung disease: remodelling, rarefaction or angiogenesis? J Anat. Oct2002;201(4):335-348.
[25] Sarada S, Himadri P, Mishra C, Geetali P, Ram MS, Ilavazhagan G. Role ofoxidative stress and NFkB in hypoxia-induced pulmonary edema. Exp Biol Med(Maywood). Sep2008;233(9):1088-1098.
[26] Doughan AK, Harrison DG, Dikalov SI. Molecular mechanisms of angiotensinII-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage andvascular endothelial dysfunction. Circ Res. Feb292008;102(4):488-496.
[27] Fike CD, Dikalova A, Slaughter JC, Kaplowitz MR, Zhang Y, Aschner JL. Reactiveoxygen species-reducing strategies improve pulmonary arterial responses to nitricoxide in piglets with chronic hypoxia-induced pulmonary hypertension. AntioxidRedox Signal. May102013;18(14):1727-1738.
[28] Fike CD, Aschner JL, Kaplowitz MR, Zhang Y, Madden JA. Reactive oxygenspecies scavengers improve voltage-gated K(+) channel function in pulmonaryarteries of newborn pigs with progressive hypoxia-induced pulmonary hypertension.Pulm Circ. Sep2013;3(3):551-563.
[29] Zhou G, Dada LA, Wu M, et al. Hypoxia-induced alveolar epithelial-mesenchymaltransition requires mitochondrial ROS and hypoxia-inducible factor1. Am J PhysiolLung Cell Mol Physiol. Dec2009;297(6):L1120-1130.
[30] Wei HL, Zhang CY, Jin HF, Tang CS, Du JB. Hydrogen sulfide regulates lungtissue-oxidized glutathione and total antioxidant capacity in hypoxic pulmonaryhypertensive rats. Acta Pharmacol Sin. Jun2008;29(6):670-679.
[31] Yang Y, Zhang BK, Liu D, et al. Sodium hydrosulfide prevents hypoxia-inducedpulmonary arterial hypertension in broilers. British poultry science.2012;53(5):608-615.
[32] Villegas LR, Kluck D, Field C, et al. Superoxide dismutase mimetic, MnTE-2-PyP,attenuates chronic hypoxia-induced pulmonary hypertension, pulmonary vascularremodeling, and activation of the NALP3inflammasome. Antioxid Redox Signal.May102013;18(14):1753-1764.
[33] Chandel NS, Trzyna WC, McClintock DS, Schumacker PT. Role of oxidants inNF-kappa B activation and TNF-alpha gene transcription induced by hypoxia andendotoxin. J Immunol. Jul152000;165(2):1013-1021.
[34] Klinke A, Moller A, Pekarova M, et al. Protective Effects of10-Nitro-Oleic Acid ina Hypoxia-Induced Murine Model of Pulmonary Hypertension. Am J Respir CellMol Biol. Feb122014.
[35] Zhang B, Niu W, Xu D, et al. Oxymatrine prevents hypoxia-andmonocrotaline-induced pulmonary hypertension in rats. Free Radic Biol Med. Jan152014.
[36] Dorfmuller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonaryarterial hypertension. Eur Respir J. Aug2003;22(2):358-363.
[37] Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonaryhypertension. Circulation.2004;109(2):159-165.
[38] Bagnato A, Rosano L. Epithelial-mesenchymal transition in ovarian cancerprogression: a crucial role for the endothelin axis. Cells Tissues Organs.2007;185(1-3):85-94.
[39] Masaki T. Historical review: Endothelin. Trends Pharmacol Sci. Apr2004;25(4):219-224.
[40] Li H, Chen SJ, Chen YF, et al. Enhanced endothelin-1and endothelin receptor geneexpression in chronic hypoxia. Journal of applied physiology (Bethesda, Md.:1985).Sep1994;77(3):1451-1459.
[41] Rubens C, Ewert R, Halank M, et al. Big endothelin-1and endothelin-1plasmalevels are correlated with the severity of primary pulmonary hypertension. Chest.Nov2001;120(5):1562-1569.
[42] Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1inpulmonary hypertension: marker or mediator of disease? Ann Intern Med. Mar151991;114(6):464-469.
[43] Yang Y, Chen D, Yuan Z, et al. Megakaryocytic leukemia1(MKL1) ties theepigenetic machinery to hypoxia-induced transactivation of endothelin-1. NucleicAcids Res. Jul12013;41(12):6005-6017.
[44] Jain R, Shaul PW, Borok Z, Willis BC. Endothelin-1induces alveolarepithelial-mesenchymal transition through endothelin type A receptor-mediatedproduction of TGF-beta1. Am J Respir Cell Mol Biol. Jul2007;37(1):38-47.
[45] Rosano L, Spinella F, Di Castro V, et al. Endothelin-1promotesepithelial-to-mesenchymal transition in human ovarian cancer cells. Cancer Res.Dec152005;65(24):11649-11657.
[46] Dias-Junior CA, Cau SB, Tanus-Santos JE.[Role of nitric oxide in the control of thepulmonary circulation: physiological, pathophysiological, and therapeuticimplications]. J Bras Pneumol. Jun2008;34(6):412-419.
[47] Naeije R, Dedobbeleer C. Pulmonary hypertension and the right ventricle in hypoxia.Exp Physiol. Aug2013;98(8):1247-1256.
[48] Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derivedgrowth factor. Physiol Rev. Oct1999;79(4):1283-1316.
[49] Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res.Sep162005;97(6):512-523.
[50]韩雅玲,肖艳平,齐岩梅,康建,徐凯,闫承慧.:胚胎血管发育早期PDGF-BB对血管平滑肌细胞趋化的影响.:中国病理生理杂志2008;24(2)251-256.
[51] Ciuclan L, Hussey MJ, Burton V, et al. Imatinib attenuates hypoxia-inducedpulmonary arterial hypertension pathology via reduction in5-hydroxytryptaminethrough inhibition of tryptophan hydroxylase1expression. Am J Respir Crit CareMed. Jan12013;187(1):78-89.
[52] Merklinger SL, Jones PL, Martinez EC, Rabinovitch M. Epidermal growth factorreceptor blockade mediates smooth muscle cell apoptosis and improves survival inrats with pulmonary hypertension. Circulation. Jul192005;112(3):423-431.
[53] Tuder RM, Cool CD, Yeager M, Taraseviciene-Stewart L, Bull TM, Voelkel NF. Thepathobiology of pulmonary hypertension. Endothelium. Clin Chest Med. Sep2001;22(3):405-418.
[54] Tamm M, Bihl M, Eickelberg O, Stulz P, Perruchoud AP, Roth M. Hypoxia-inducedinterleukin-6and interleukin-8production is mediated by platelet-activating factorand platelet-derived growth factor in primary human lung cells. Am J Respir CellMol Biol. Oct1998;19(4):653-661.
[55] Teyssier C, Le Romancer M, Sentis S, Jalaguier S, Corbo L, Cavailles V. Proteinarginine methylation in estrogen signaling and estrogen-related cancers. TrendsEndocrinol Metab. Mar2010;21(3):181-189.
[56] Wilkins MR, Wharton J, Grimminger F, Ghofrani HA. Phosphodiesterase inhibitorsfor the treatment of pulmonary hypertension. Eur Respir J. Jul2008;32(1):198-209.
[57] Rashid M, Fahim M, Kotwani A. Efficacy of tadalafil in chronic hypobarichypoxia-induced pulmonary hypertension: possible mechanisms. Fundamental&clinical pharmacology. Jun2013;27(3):271-278.
[58] Tsai BM, Turrentine MW, Sheridan BC, et al. Differential effects ofphosphodiesterase-5inhibitors on hypoxic pulmonary vasoconstriction andpulmonary artery cytokine expression. Ann Thorac Surg. Jan2006;81(1):272-278.
[59] Christman BW, McPherson CD, Newman JH, et al. An imbalance between theexcretion of thromboxane and prostacyclin metabolites in pulmonary hypertension.N Engl J Med. Jul91992;327(2):70-75.
[60] Takemiya K, Kai H, Yasukawa H, Tahara N, Kato S, Imaizumi T. Mesenchymalstem cell-based prostacyclin synthase gene therapy for pulmonary hypertension rats.Basic Res Cardiol. May2010;105(3):409-417.
[61] Bonnet S, Archer SL. Potassium channel diversity in the pulmonary arteries andpulmonary veins: implications for regulation of the pulmonary vasculature in healthand during pulmonary hypertension. Pharmacol Ther. Jul2007;115(1):56-69.
[62] Yuan JX, Aldinger AM, Juhaszova M, et al. Dysfunctional voltage-gated K+channels in pulmonary artery smooth muscle cells of patients with primarypulmonary hypertension. Circulation. Oct61998;98(14):1400-1406.
[63] Dong L, Li Y, Hu H, et al. Potential therapeutic targets for hypoxia-inducedpulmonary artery hypertension. J Transl Med. Feb82014;12(1):39.
[64] Nitta CH, Osmond DA, Herbert LM, et al. Role of ASIC1in the development ofchronic hypoxia-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol.Jan12014;306(1):H41-52.
[65] Cheever KH. An overview of pulmonary arterial hypertension: risks, pathogenesis,clinical manifestations, and management. J Cardiovasc Nurs. Mar-Apr2005;20(2):108-116; quiz117-108.
[66] Crosswhite P, Sun Z. Nitric oxide, oxidative stress and inflammation in pulmonaryarterial hypertension. J Hypertens. Feb2010;28(2):201-212.
[67] Wang Y, Wysocka J, Sayegh J, et al. Human PAD4regulates histone argininemethylation levels via demethylimination. Science.2004;306(5694):279-283.
[68] van Dijk TB, Gillemans N, Stein C, et al. Friend of Prmt1, a novel chromatin targetof protein arginine methyltransferases. Mol Cell Biol. Jan2010;30(1):260-272.
[69] Huang X, Fan R, Lu Y, et al. Regulatory effect of AMP-activated protein kinase onpulmonary hypertension induced by chronic hypoxia in rats: in vivo and in vitrostudies. Mol Biol Rep. Feb252014.
[70] Shimizu T, Fukumoto Y, Tanaka S, Satoh K, Ikeda S, Shimokawa H. Crucial role ofROCK2in vascular smooth muscle cells for hypoxia-induced pulmonaryhypertension in mice. Arterioscler Thromb Vasc Biol. Dec2013;33(12):2780-2791.
[71] Malczyk M, Veith C, Fuchs B, et al. Classical transient receptor potential channel1in hypoxia-induced pulmonary hypertension. Am J Respir Crit Care Med. Dec152013;188(12):1451-1459.
[72] Xu D, Niu W, Luo Y, et al. Endogenous estrogen attenuates hypoxia-inducedpulmonary hypertension by inhibiting pulmonary arterial vasoconstriction andpulmonary arterial smooth muscle cells proliferation. International journal ofmedical sciences.2013;10(6):771-781.
[73] Horita H, Furgeson SB, Ostriker A, et al. Selective inactivation of PTEN in smoothmuscle cells synergizes with hypoxia to induce severe pulmonary hypertension.Journal of the American Heart Association. Jun2013;2(3):e000188.
[74] Nie X, Shi Y, Yu W, Xu J, Hu X, Du Y. Phosphorylation of PTEN increase inpathological right ventricular hypertrophy in rats with chronic hypoxia inducedpulmonary hypertension. Chin Med J (Engl).2014;127(2):338-342.
[75] Yi ES, Kim H, Ahn H, et al. Distribution of obstructive intimal lesions and theircellular phenotypes in chronic pulmonary hypertension. A morphometric andimmunohistochemical study. Am J Respir Crit Care Med. Oct2000;162(4Pt1):1577-1586.
[76] Frid MG, Brunetti JA, Burke DL, et al. Hypoxia-induced pulmonary vascularremodeling requires recruitment of circulating mesenchymal precursors of amonocyte/macrophage lineage. Am J Pathol. Feb2006;168(2):659-669.
[77] Stenmark KR, Davie N, Frid M, Gerasimovskaya E, Das M. Role of the adventitia inpulmonary vascular remodeling. Physiology (Bethesda). Apr2006;21:134-145.
[78] Quinn AM, Bedford MT, Espejo A, et al. A homogeneous method for investigationof methylation-dependent protein-protein interactions in epigenetics. Nucleic AcidsRes. Jan2010;38(2):e11.
[79] Morrell NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonaryarterial hypertension. J Am Coll Cardiol. Jun302009;54(1Suppl):S20-31.
[80] Li XW, Du J, Hu GY, et al. Fluorofenidone attenuates vascular remodeling inhypoxia-induced pulmonary hypertension of rats. Can J Physiol Pharmacol. Jan2014;92(1):58-69.
[81] Goumans MJ, Liu Z, ten Dijke P. TGF-beta signaling in vascular biology anddysfunction. Cell Res. Jan2009;19(1):116-127.
[82] Zhu PC, Huang L, Ge XN, Yan F, Wu RL, Ao QL. Transdifferentiation of pulmonaryarteriolar endothelial cells into smooth muscle-like cells regulated by myocardininvolved in hypoxia-induced pulmonary vascular remodelling. International Journalof Experimental Pathology. Dec2006;87(6):463-474.
[83] Carvajal G, Rodriguez-Vita J, Rodrigues-Diez R, et al. Angiotensin II activates theSmad pathway during epithelial mesenchymal transdifferentiation. Kidney Int. Sep2008;74(5):585-595.
[84] Wolf G. Renal injury due to renin-angiotensin-aldosterone system activation of thetransforming growth factor-beta pathway. Kidney Int. Dec2006;70(11):1914-1919.
[85] High FA, Zhang M, Proweller A, et al. An essential role for Notch in neural crestduring cardiovascular development and smooth muscle differentiation. J Clin Invest.Feb2007;117(2):353-363.
[86] Morrow D, Guha S, Sweeney C, et al. Notch and vascular smooth muscle cellphenotype. Circ Res. Dec52008;103(12):1370-1382.
[87] Doi H, Iso T, Sato H, et al. Jagged1-selective notch signaling induces smoothmuscle differentiation via a RBP-Jkappa-dependent pathway. J Biol Chem. Sep292006;281(39):28555-28564.
[88] Noseda M, McLean G, Niessen K, et al. Notch activation results in phenotypic andfunctional changes consistent with endothelial-to-mesenchymal transformation. CircRes. Apr162004;94(7):910-917.
[89] Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilicalcord blood. Br J Haematol. Apr2000;109(1):235-242.
[90] Silva GV, Litovsky S, Assad JA, et al. Mesenchymal stem cells differentiate into anendothelial phenotype, enhance vascular density, and improve heart function in acanine chronic ischemia model. Circulation. Jan182005;111(2):150-156.
[91] Nikolova-Krstevski V, Bhasin M, Otu HH, Libermann T, Oettgen P. Gene expressionanalysis of embryonic stem cells expressing VE-cadherin (CD144) duringendothelial differentiation. BMC Genomics.2008;9:240.
[92] Abedin M, Tintut Y, Demer LL. Mesenchymal stem cells and the artery wall. CircRes. Oct12004;95(7):671-676.
[93] Hamano K, Li TS.[Cell-based therapeutic angiogenesis for the treatment ofischemic disease]. Nippon Geka Gakkai Zasshi. Aug2004;105(8):464-468.
[94] Fuchs S, Baffour R, Zhou YF, et al. Transendocardial delivery of autologous bonemarrow enhances collateral perfusion and regional function in pigs with chronicexperimental myocardial ischemia. J Am Coll Cardiol. May2001;37(6):1726-1732.
[95] Ball MK, Waypa GB, Mungai PT, et al. Regulation of Hypoxia-induced PulmonaryHypertension by Vascular Smooth Muscle Hypoxia-Inducible Factor-1alpha. Am JRespir Crit Care Med. Feb12014;189(3):314-324.
[96] Yan J, Shen Y, Wang Y, Li BB. Increased expression of hypoxia-induciblefactor-1alpha in proliferating neointimal lesions in a rat model of pulmonary arterialhypertension. Am J Med Sci. Feb2013;345(2):121-128.
[97] Shan F, Li J, Huang QY. HIF-1Alpha-Induced Up-Regulation of miR-9Contributesto Phenotypic Modulation in Pulmonary Artery Smooth Muscle Cells DuringHypoxia. J Cell Physiol. Feb252014.
[98] Kim SY, Choi YJ, Joung SM, Lee BH, Jung YS, Lee JY. Hypoxic stress up-regulatesthe expression of Toll-like receptor4in macrophages via hypoxia-inducible factor.Immunology. Apr2010;129(4):516-524.
[99] Zimnicka AM, Tang H, Guo Q, et al. Upregulated copper transporters inhypoxia-induced pulmonary hypertension. PLoS One.2014;9(3):e90544.
[100] Yue J, Guan J, Wang X, et al. MicroRNA-206is involved in hypoxia-inducedpulmonary hypertension through targeting of the HIF-1alpha/Fhl-1pathway. LabInvest. Jul2013;93(7):748-759.
[101] Hansmann G, Wagner RA, Schellong S, et al. Pulmonary arterial hypertension islinked to insulin resistance and reversed by peroxisome proliferator-activatedreceptor-gamma activation. Circulation. Mar132007;115(10):1275-1284.
[102] Rabinovitch M. PPARgamma and the pathobiology of pulmonary arterialhypertension. Adv Exp Med Biol.2010;661:447-458.
[103] Li M, Li Z, Sun X, et al. Heme oxygenase-1/p21WAF1mediates peroxisomeproliferator-activated receptor-gamma signaling inhibition of proliferation of ratpulmonary artery smooth muscle cells. FEBS J. Mar2010;277(6):1543-1550.
2Yidiz P. Molecular mechanisms of pulmonary hypertension. Clinica Chimica Acta. May2009;403(1-2):9-16.
Ward JP, McMurtry IF. Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension:new findings for an old problem. Curr Opin Pharmacol. Jun2009;9(3):287-296.
4Rabinovitch M, Bothwell T, Hayakawa BN, Williams WG, Trusler GA, Rowe RD, Olley PM, Cutz E: Pulmonary arteryendothelial abnormalities in patients with congenital heart defects and pulmonary hypertension. A correlation of lightwith scanning electron microscopy and transmission electron microscopy. Lab Invest1986,55(6):632-653.
5陈小容,邹霞英:缺氧性肺动脉高压大鼠肺血管内皮细胞的变化.中国病理生理杂志1996,12(6):608-611.
1Botto L, Beretta E, Daffara R, Miserocchi G, Palestini P: Biochemical and morphological changes in endothelial cellsin response to hypoxic interstitial edema. Respir Res2006,7:7.
2Bagnato A, Rosano L. Epithelial-mesenchymal transition in ovarian cancer progression: a crucial role for theendothelin axis. Cells Tissues Organs.2007;185(1-3):85-94.
3Li H, Chen SJ, Chen YF, et al. Enhanced endothelin-1and endothelin receptor gene expression in chronic hypoxia.Journal of applied physiology (Bethesda, Md.:1985). Sep1994;77(3):1451-1459.
4Rubens C, Ewert R, Halank M, et al. Big endothelin-1and endothelin-1plasma levels are correlated with the severityof primary pulmonary hypertension. Chest. Nov2001;120(5):1562-1569.
5Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1in pulmonary hypertension: marker ormediator of disease? Ann Intern Med. Mar151991;114(6):464-469.
6Yamashita K, Discher DJ, Hu J, Bishopric NH, Webster KA: Molecular regulation of the endothelin-1gene by hypoxia.Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP. J Biol Chem2001,276(16):12645-12653.
7Yang Y, Chen D, Yuan Z, et al. Megakaryocytic leukemia1(MKL1) ties the epigenetic machinery to hypoxia-inducedtransactivation of endothelin-1. Nucleic Acids Res. Jul12013;41(12):6005-6017.
8Savale L, Tu L, Rideau D, Izziki M, Maitre B, Adnot S, Eddahibi S: Impact of interleukin-6on hypoxia-inducedpulmonary hypertension and lung inflammation in mice. Respir Res2009,10:6.
9Burke DL, Frid MG, Kunrath CL, Karoor V, Anwar A, Wagner BD, Strassheim D, Stenmark KR: Sustained hypoxiapromotes the development of a pulmonary artery-specific chronic inflammatory microenvironment. Am J Physiol LungCell Mol Physiol2009,297(2):L238-250.
10Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB: Interleukin-6overexpression inducespulmonary hypertension. Circ Res2009,104(2):236-244,228p following244.
1Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT, Roedersheimer MT, van Rooijen N, StenmarkKR: Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of amonocyte/macrophage lineage. Am J Pathol2006,168(2):659-669.
2Barreiro O, Martin P, Gonzalez-Amaro R, Sanchez-Madrid F: Molecular cues guiding inflammatory responses.Cardiovasc Res2010,86(2):174-182.
3He P: Leucocyte/endothelium interactions and microvessel permeability: coupled or uncoupled? Cardiovasc Res2010,87(2):281-290.
4Winning S, Splettstoesser F, Fandrey J, Frede S: Acute hypoxia induces HIF-independent monocyte adhesion toendothelial cells through increased intercellular adhesion molecule-1expression: the role of hypoxic inhibition of prolylhydroxylase activity for the induction of NF-kappa B. J Immunol2010,185(3):1786-1793.
5Golembeski SM, West J, Tada Y, Fagan KA: Interleukin-6causes mild pulmonary hypertension and augmentshypoxia-induced pulmonary hypertension in mice. Chest2005,128(6Suppl):572S-573S.
6Csiszar A, Wang M, Lakatta EG, Ungvari Z: Inflammation and endothelial dysfunction during aging: role ofNF-kappaB. Journal of applied physiology (Bethesda, Md:1985)2008,105(4):1333-1341.
7Culver C, Sundqvist A, Mudie S, Melvin A, Xirodimas D, Rocha S: Mechanism of hypoxia-induced NF-kappaB. MolCell Biol2010,30(20):4901-4921.
8Tong Q, Zheng L, Lin L, Li B, Wang D, Li D: Hypoxia-induced mitogenic factor promotes vascular sion molecule-1expression via the PI-3K/Akt-NF-kappaB signaling pathway. Am J Respir Cell Mol Biol6,35(4):444-456.
1Hargreaves DC, Crabtree GR: ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res2011,21(3):396-420.
Schnitzler G, Sif S, Kingston RE: Human SWI/SNF interconverts a nucleosome between its base state and a stableremodeled state. Cell1998,94(1):17-27.
Takeuchi JK, Lou X, Alexander JM, Sugizaki H, Delgado-Olguin P, Holloway AK, Mori AD, Wylie JN, Munson C,Zhu Y et al: Chromatin remodelling complex dosage modulates transcription factor function in heart development. NatCommun2011,2:187.
Khavari PA, Peterson CL, Tamkun JW, Mendel DB, Crabtree GR: BRG1contains a conserved domain of theSWI2/SNF2family necessary for normal mitotic growth and transcription. Nature1993,366(6451):170-174.
Reyes JC, Barra J, Muchardt C, Camus A, Babinet C, Yaniv M: Altered control of cellular proliferation in the absencef mammalian brahma (SNF2alpha). EMBO J1998,17(23):6979-6991.
Rodriguez-Nieto S, Sanchez-Cespedes M: BRG1and LKB1: tales of two tumor suppressor genes on chromosome19pand lung cancer. Carcinogenesis2009,30(4):547-554.
Trotter KW, Archer TK: Nuclear receptors and chromatin remodeling machinery. Mol Cell Endocrinol2007,265-266:162-167.
Yoo AS, Crabtree GR: ATP-dependent chromatin remodeling in neural development. Curr Opin Neurobiol2009,19(2):120-126.
Saladi SV, Keenen B, Marathe HG, Qi H, Chin KV, de la Serna IL: Modulation of extracellular matrix/adhesionmolecule expression by BRG1is associated with increased melanoma invasiveness. Mol Cancer2010,9:280.
Zhang L, Zhang Q, Jones K, Patel M, Gong F: The chromatin remodeling factor BRG1stimulates nucleotide excisionrepair by facilitating recruitment of XPC to sites of DNA damage. Cell Cycle2009,8(23):3953-3959.
Dykhuizen EC, Hargreaves DC, Miller EL, Cui K, Korshunov A, Kool M, Pfister S, Cho YJ, Zhao K, Crabtree GR:BAF complexes facilitate decatenation of DNA by topoisomerase IIalpha. Nature2013,497(7451):624-627.
1Kadam S, Emerson BM: Transcriptional specificity of human SWI/SNF BRG1and BRM chromatin remodelingcomplexes. Mol Cell2003,11(2):377-389.
2Naito M, Zager RA, Bomsztyk K: BRG1increases transcription of proinflammatory genes in renal ischemia. J Am SocNephrol2009,20(8):1787-1796.
3Wang F, Zhang R, Beischlag TV, Muchardt C, Yaniv M, Hankinson O: Roles of Brahma and Brahma/SWI2-relatedgene1in hypoxic induction of the erythropoietin gene. J Biol Chem2004,279(45):46733-46741.
4Zhou J, Zhang M, Fang H, El-Mounayri O, Rodenberg JM, Imbalzano AN, Herring BP: The SWI/SNF chromatinremodeling complex regulates myocardin-induced smooth muscle-specific gene expression. Arterioscler Thromb VascBiol2009,29(6):921-928.
5Limpert AS, Bai S, Narayan M, Wu J, Yoon SO, Carter BD, Lu QR: NF-kappaB Forms a Complex with the ChromatinRemodeler BRG1to Regulate Schwann Cell Differentiation. J Neurosci2013,33(6):2388-2397.
6Zhang M, Fang H, Zhou J, Herring BP: A novel role of Brg1in the regulation of SRF/MRTFA-dependent smoothmuscle-specific gene expression. J Biol Chem2007,282(35):25708-25716.
7Sena JA, Wang L, Hu CJ. BRG1and BRM chromatin-remodeling complexes regulate the hypoxia response by actingas coactivators for a subset of hypoxia-inducible transcription factor target genes. Mol Cell Biol. Oct2013;33(19):3849-3863.
Fang F, Chen D, Yu L, Dai X, Yang Y, Tian W, Cheng X, Xu H, Weng X, Fang M et al: Proinflammatory stimuli engageBrahma related gene1and Brahma in endothelial injury. Circ Res2013,113(8):986-996.
1Mohrmann L, Verrijzer CP: Composition and functional specificity of SWI2/SNF2class chromatin remodelingcomplexes. Biochim Biophys Acta2005,1681(2-3):59-73.
2Trotter KW, Archer TK: The BRG1transcriptional coregulator. Nucl Recept Signal2008,6:e004.
Phelan ML, Sif S, Narlikar GJ, Kingston RE: Reconstitution of a core chromatin remodeling complex from SWI/SNFsubunits. Mol Cell1999,3(2):247-253.
1Hang CT, Yang J, Han P, Cheng HL, Shang C, Ashley E, Zhou B, Chang CP: Chromatin regulation by Brg1underliesheart muscle development and disease. Nature2010,466(7302):62-67.
Jiang C, Liu F, Luo Y, Li P, Chen J, Xu G, Wang Y, Li X, Huang J, Gao Y: Gene expression profiling of high altitudepolycythemia in Han Chinese migrating to the Qinghai-Tibetan plateau. Mol Med Rep2012,5(1):287-293.
Ariumi Y, Serhan F, Turelli P, Telenti A, Trono D: The integrase interactor1(INI1) proteins facilitate Tat-mediatedhuman immunodeficiency virus type1transcription. Retrovirology2006,3:47.
1Cao Y, Vo T, Millien G, Tagne JB, Kotton D, Mason RJ, Williams MC, Ramirez MI: Epigenetic mechanisms modulatethyroid transcription factor1-mediated transcription of the surfactant protein B gene. J Biol Chem2010,285(3):2152-2164.
2Coisy-Quivy M, Disson O, Roure V, Muchardt C, Blanchard JM, Dantonel JC: Role for Brm in cell growth control.Cancer Res2006,66(10):5069-5076.
3Zhang H, Gao Y, Zhao F, Dai Z, Meng T, Tu S, Yan Y: Hydrogen sulfide reduces mRNA and protein levels of beta-siteamyloid precursor protein cleaving enzyme1in PC12cells. Neurochem Int2011,58(2):169-175.
1高钰琪.高原军事医学.重庆：重庆出版社.2004
1Hou X, Chen J, Luo Y, Liu F, Xu G, Gao Y. Silencing of STIM1attenuates hypoxia-induced PASMCs proliferation viainhibition of the SOC/Ca2+/NFAT pathway. Respir Res.2013;14:2.
Phelan ML, Sif S, Narlikar GJ, Kingston RE: Reconstitution of a core chromatin remodeling complex from SWI/SNFsubunits. Mol Cell1999,3(2):247-253.
1Vachtenheim J, Ondrusova L, Borovansky J: SWI/SNF chromatin remodeling complex is critical for the expression ofmicrophthalmia-associated transcription factor in melanoma cells. Biochem Bioph Res Co2010,392(3):454-459.
2Miller SA, Mohn SE, Weinmann AS: Jmjd3and UTX play a demethylase-independent role in chromatin remodeling toregulate T-box family member-dependent gene expression. Mol Cell2010,40(4):594-605.
3Zhang HS, Gavin M, Dahiya A, Postigo AA, Ma D, Luo RX, Harbour JW, Dean DC: Exit from G1and S phase of thecell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell2000,101(1):79-89.
4Geiman TM, Sankpal UT, Robertson AK, Zhao Y, Zhao Y, Robertson KD: DNMT3B interacts with hSNF2H chromatinremodeling enzyme, HDACs1and2, and components of the histone methylation system. Biochem Biophys Res Commun2004,318(2):544-555.
5Sluiter W, Pietersma A, Lamers JM, Koster JF: Leukocyte adhesion molecules on the vascular endothelium: their rolein the pathogenesis of cardiovascular disease and the mechanisms underlying their expression. J Cardiovasc Pharmacol1993,22Suppl4:S37-44.
1de La Serna IL, Carlson KA, Hill DA, Guidi CJ, Stephenson RO, Sif S, Kingston RE, Imbalzano AN: MammalianSWI-SNF complexes contribute to activation of the hsp70gene. Mol Cell Biol2000,20(8):2839-2851.
2Voraberger G, Schafer R, Stratowa C: Cloning of the human gene for intercellular adhesion molecule1and analysis ofits5'-regulatory region. Induction by cytokines and phorbol ester. J Immunol1991,147(8):2777-2786.
3Munoz C, Castellanos MC, Alfranca A, Vara A, Esteban MA, Redondo JM, de Landazuri MO: Transcriptionalup-regulation of intracellular adhesion molecule-1in human endothelial cells by the antioxidant pyrrolidinedithiocarbamate involves the activation of activating protein-1. J Immunol1996,157(8):3587-3597.
Yu G, Rux AH, Ma P, Bdeir K, Sachais BS: Endothelial expression of E-selectin is induced by the platelet-specificchemokine platelet factor4through LRP in an NF-kappaB-dependent manner. Blood2005,105(9):3545-3551.
1Jeong KW, Lee YH, Stallcup MR: Recruitment of the SWI/SNF chromatin remodeling complex to steroidhormone-regulated promoters by nuclear receptor coactivator flightless-I. J Biol Chem2009,284(43):29298-29309.
2Treand C, du Chene I, Bres V, Kiernan R, Benarous R, Benkirane M, Emiliani S: Requirement for SWI/SNFchromatin-remodeling complex in Tat-mediated activation of the HIV-1promoter. EMBO J2006,25(8):1690-1699.
3Verma UN, Surabhi RM, Schmaltieg A, Becerra C, Gaynor RB: Small interfering RNAs directed against beta-catenininhibit the in vitro and in vivo growth of colon cancer cells. Clin Cancer Res2003,9(4):1291-1300.
1Bito T, Roy S, Sen CK, Shirakawa T, Gotoh A, Ueda M, Ichihashi M, Packer L: Flavonoids differentially regulate IFNgamma-induced ICAM-1expression in human keratinocytes: molecular mechanisms of action. FEBS Lett2002,520(1-3):145-152.
Hattori Y, Suzuki K, Hattori S, Kasai K: Metformin inhibits cytokine-induced nuclear factor kappaB activation viaAMP-activated protein kinase activation in vascular endothelial cells. Hypertension2006,47(6):1183-1188.
1Fang F, Yang Y, Yuan Z, Gao Y, Zhou J, Chen Q, Xu Y: Myocardin-Related Transcription Factor A MediatesOxLDL-Induced Endothelial Injury. Circ Res2011.
1Ritchie MH, Fillmore RA, Lausch RN, Oakes JE: A role for NF-kappa B binding motifs in the differential induction ofchemokine gene expression in human corneal epithelial cells. Invest Ophthalmol Vis Sci2004,45(7):2299-2305.
2Liu M, Kluger MS, D'Alessio A, Garcia-Cardena G, Pober JS: Regulation of arterial-venous differences in tumornecrosis factor responsiveness of endothelial cells by anatomic context. Am J Pathol2008,172(4):1088-1099.
1Winning S, Splettstoesser F, Fandrey J, Frede S: Acute hypoxia induces HIF-independent monocyte adhesion toendothelial cells through increased intercellular adhesion molecule-1expression: the role of hypoxic inhibition of prolylhydroxylase activity for the induction of NF-kappa B. J Immunol2010,185(3):1786-1793.
1Xu Y, Zhang J, Chen XB: The activity of p53is differentially regulated by Brm-and Brg1-containing SWI/SNFchromatin remodeling complexes. J Biol Chem2007,282(52):37429-37435.
2Reyes JC, Barra J, Muchardt C, Camus A, Babinet C, Yaniv M: Altered control of cellular proliferation in the absenceof mammalian brahma (SNF2alpha). EMBO J1998,17(23):6979-6991.
3Phelan ML, Sif S, Narlikar GJ, Kingston RE: Reconstitution of a core chromatin remodeling complex from SWI/SNFsubunits. Mol Cell1999,3(2):247-253.
4Halliday GM, Bock VL, Moloney FJ, Lyons JG: SWI/SNF: a chromatin-remodelling complex with a role incarcinogenesis. Int J Biochem Cell Biol2009,41(4):725-728.
5Monahan BJ, Villen J, Marguerat S, Bahler J, Gygi SP, Winston F: Fission yeast SWI/SNF and RSC complexes showcompositional and functional differences from budding yeast. Nat Struct Mol Biol2008,15(8):873-880.
1Zhang B, Chambers KJ, Faller DV, Wang S: Reprogramming of the SWI/SNF complex for co-activation orco-repression in prohibitin-mediated estrogen receptor regulation. Oncogene2007,26(50):7153-7157.
2Ramirez-Carrozzi VR, Nazarian AA, Li CC, Gore SL, Sridharan R, Imbalzano AN, Smale ST: Selective andantagonistic functions of SWI/SNF and Mi-2beta nucleosome remodeling complexes during an inflammatory response.Genes Dev2006,20(3):282-296.
3Naito M, Zager RA, Bomsztyk K: BRG1increases transcription of proinflammatory genes in renal ischemia. J Am SocNephrol2009,20(8):1787-1796.
4Angelov D, Lenouvel F, Hans F, Muller CW, Bouvet P, Bednar J, Moudrianakis EN, Cadet J, Dimitrov S: The histoneoctamer is invisible when NF-kappaB binds to the nucleosome. J Biol Chem2004,279(41):42374-42382.
1Jenuwein T, Allis CD: Translating the histone code. Science2001,293(5532):1074-1080.
1Langleben D: Endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Clin Chest Med2007,28(1):117-125, viii.
2Goerre S, Wenk M, Bartsch P, Luscher TF, Niroomand F, Hohenhaus E, Oelz O, Reinhart WH: Endothelin-1inpulmonary hypertension associated with high-altitude exposure. Circulation1995,91(2):359-364.
3Modesti PA, Vanni S, Morabito M, Modesti A, Marchetta M, Gamberi T, Sofi F, Savia G, Mancia G, Gensini GF et al:Role of endothelin-1in exposure to high altitude: Acute Mountain Sickness and Endothelin-1(ACME-1) study.Circulation2006,114(13):1410-1416.
Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ:Expression of endothelin-1in the lungs of patients with pulmonary hypertension. N Engl J Med1993,328(24):1732-1739.
5Yamashita K, Discher DJ, Hu J, Bishopric NH, Webster KA: Molecular regulation of the endothelin-1gene by hypoxia.Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP. J Biol Chem2001,276(16):12645-12653.
6Yang Y, Chen D, Yuan Z, et al. Megakaryocytic leukemia1(MKL1) ties the epigenetic machinery to hypoxia-inducedtransactivation of endothelin-1. Nucleic Acids Res. Jul12013;41(12):6005-6017.
Zhang M, Fang H, Zhou J, Herring BP: A novel role of Brg1in the regulation of SRF/MRTFA-dependent smoothmuscle-specific gene expression. J Biol Chem2007,282(35):25708-25716.
1Glenn DJ, Rahmutula D, Nishimoto M, Liang F, Gardner DG: Atrial natriuretic peptide suppresses endothelin geneexpression and proliferation in cardiac fibroblasts through a GATA4-dependent mechanism. Cardiovasc Res2009,84(2):209-217.
Vachtenheim J, Ondrusova L, Borovansky J: SWI/SNF chromatin remodeling complex is critical for the expression ofmicrophthalmia-associated transcription factor in melanoma cells. Biochem Bioph Res Co2010,392(3):454-459.
1Mawji IA, Robb GB, Tai SC, Marsden PA: Role of the3'-untranslated region of human endothelin-1in vascularendothelial cells. Contribution to transcript lability and the cellular heat shock response. J Biol Chem2004,279(10):8655-8667.
1Budhiraja R, Tuder RM, Hassoun PM: Endothelial dysfunction in pulmonary hypertension. Circulation2004,109(2):159-165.
2Yuan Z, Chen J, Chen D, Xu G, Xia M, Xu Y, Gao Y: Megakaryocytic Leukemia1(MKL1) Regulates Hypoxia InducedPulmonary Hypertension in Rats. PLoS One2014,9(3):e83895.
3Yang Y, Chen D, Yuan Z, et al. Megakaryocytic leukemia1(MKL1) ties the epigenetic machinery to hypoxia-inducedtransactivation of endothelin-1. Nucleic Acids Res. Jul12013;41(12):6005-6017.
4Zager RA, Johnson AC: Renal ischemia-reperfusion injury upregulates histone-modifying enzyme systems and altershistone expression at proinflammatory/profibrotic genes. Am J Physiol Renal Physiol2009,296(5): F1032-1041.
5Zhou J, Zhang M, Fang H, El-Mounayri O, Rodenberg JM, Imbalzano AN, Herring BP: The SWI/SNF chromatinremodeling complex regulates myocardin-induced smooth muscle-specific gene expression. Arterioscler Thromb VascBiol2009,29(6):921-928.
1Fang F, Chen D, Yu L, Dai X, Yang Y, Tian W, Cheng X, Xu H, Weng X, Fang M et al: Proinflammatory stimuli engageBrahma related gene1and Brahma in endothelial injury. Circ Res2013,113(8):986-996.
1Chen J, Tan B, Karteris E, Zervou S, Digby J, Hillhouse EW, Vatish M, Randeva HS: Secretion of adiponectin byhuman placenta: differential modulation of adiponectin and its receptors by cytokines. Diabetologia2006,49(6):1292-1302.
Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, Mirrakhimov MM, Aldashev A, Wilkins MR:Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation2001,104(4):424-428.
1Seldon MP, Silva G, Pejanovic N, Larsen R, Gregoire IP, Filipe J, Anrather J, Soares MP: Heme oxygenase-1inhibitsthe expression of adhesion molecules associated with endothelial cell activation via inhibition of NF-kappaB RelAphosphorylation at serine276. J Immunol2007,179(11):7840-7851.
2Ren G, Zhao X, Zhang L, Zhang J, L'Huillier A, Ling W, Roberts AI, Le AD, Shi S, Shao C et al: Inflammatorycytokine-induced intercellular adhesion molecule-1and vascular cell adhesion molecule-1in mesenchymal stem cells arecritical for immunosuppression. J Immunol2010,184(5):2321-2328.
3Winkler F, Koedel U, Kastenbauer S, Pfister HW: Differential expression of nitric oxide synthases in bacterialmeningitis: role of the inducible isoform for blood-brain barrier breakdown. The Journal of infectious diseases2001,183(12):1749-1759.
1Mushaben EM, Hershey GK, Pauciulo MW, Nichols WC, Le Cras TD. Chronic allergic inflammation causes vascularremodeling and pulmonary hypertension in BMPR2hypomorph and wild-type mice. PLoS One.2012;7(3):e32468.
Tabima DM, Hacker TA, Chesler NC: Measuring right ventricular function in the normal and hypertensive mousehearts using admittance-derived pressure-volume loops. Am J Physiol Heart Circ Physiol2010,299(6):H2069-2075.
1Tabima DM, Hacker TA, Chesler NC: Measuring right ventricular function in the normal and hypertensive mousehearts using admittance-derived pressure-volume loops. Am J Physiol Heart Circ Physiol2010,299(6):H2069-2075.
Zhang B, Shen M, Xu M, Liu LL, Luo Y, Xu DQ, Wang YX, Liu ML, Liu Y, Dong HY et al: Role of macrophage migrationinhibitory factor in the proliferation of smooth muscle cell in pulmonary hypertension. Mediators Inflamm2012,2012:840737.
Arnaud C, Beguin PC, Lantuejoul S, Pepin JL, Guillermet C, Pelli G, Burger F, Buatois V, Ribuot C, Baguet JP et al:The inflammatory preatherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5inhibition. Am J Respir Crit Care Med2011,184(6):724-731.
Weber C, Zernecke A, Libby P: The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons frommouse models. Nat Rev Immunol2008,8(10):802-815.
Hang CT, Yang J, Han P, Cheng HL, Shang C, Ashley E, Zhou B, Chang CP: Chromatin regulation by Brg1underliesheart muscle development and disease. Nature2010,466(7302):62-67.
Tian W, Xu H, Fang F, Chen Q, Xu Y, Shen A: Brahma-related gene1bridges epigenetic regulation of proinflammatorycytokine production to steatohepatitis in mice. Hepatology2013,58(2):576-588.
1Glaros S, Cirrincione GM, Palanca A, Metzger D, Reisman D: Targeted knockout of BRG1potentiates lung cancerdevelopment. Cancer Res2008,68(10):3689-3696.
Reisman D, Glaros S, Thompson EA: The SWI/SNF complex and cancer. Oncogene2009,28(14):1653-1668.
3Vachtenheim J, Ondrusova L, Borovansky J: SWI/SNF chromatin remodeling complex is critical for the expression ofmicrophthalmia-associated transcription factor in melanoma cells. Biochem Bioph Res Co2010,392(3):454-459.
Ross S, Cheung E, Petrakis TG, Howell M, Kraus WL, Hill CS: Smads orchestrate specific histone modifications andchromatin remodeling to activate transcription. EMBO J2006,25(19):4490-4502
1高钰琪.高原军事医学.重庆出版社.2004.
2Sakao S, Tatsumi K. Vascular remodeling in pulmonary arterial hypertension: multiple cancer-like pathways andpossible treatment modalities. Int J Cardiol. Feb172011;147(1):4-12.
3Jeffery TK, Wanstall JC. Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonaryhypertension. Pharmacol Ther. Oct2001;92(1):1-20.
Mowen K, Tang J, Zhu W, et al. Arginine methylation of STAT1modulates IFNalpha/beta-induced transcription. Cell.2001;104(5):731-741.
1高钰琪.高原军事医学.重庆出版社.2004.
Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J AmColl Cardiol. Jun302009;54(1Suppl):S10-19.
Van Hung T, Emoto N, Vignon-Zellweger N, et al. Inhibition of vascular endothelial growth factor receptor underhypoxia causes severe, human-like pulmonary arterial hypertension in mice: Potential roles of interleukin-6andendothelin. Life Sci. Jan82014.
Burke DL, Frid MG, Kunrath CL, et al. Sustained hypoxia promotes the development of a pulmonary artery-specificchronic inflammatory microenvironment. Am J Physiol Lung Cell Mol Physiol. Aug2009;297(2):L238-250.
Tuder RM, Voelkel NF. Pulmonary hypertension and inflammation. Journal of Laboratory and Clinical Medicine.1998;132(1):16-24.
Humbert M, Monti G, Brenot F, et al. Increased interleukin-1and interleukin-6serum concentrations in severe primarypulmonary hypertension. Am J Respir Crit Care Med. May1995;151(5):1628-1631.
Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6overexpression inducespulmonary hypertension. Circ Res. Jan302009;104(2):236-244,228p following244.
李尚师,李素芝,郑必海,宋娟,李红,曲涛.:快速进入高原者血清NO及白介素-1,6,8含量变化观察.:中国煤炭工业医学杂志2007;10(9)1055-1056.
Matsuda N, Hattori Y. Systemic inflammatory response syndrome (SIRS): molecular pathophysiology and gene therapy.J Pharmacol Sci. Jul2006;101(3):189-198.
Young KC, Hussein SM, Dadiz R, et al. Toll-like receptor4-deficient mice are resistant to chronic hypoxia-inducedpulmonary hypertension. Exp Lung Res. Mar2010;36(2):111-119.
1Quarck R, Nawrot T, Meyns B, Delcroix M. C-reactive protein: a new predictor of adverse outcome in pulmonaryarterial hypertension. J Am Coll Cardiol. Apr72009;53(14):1211-1218.
2Li J, Li JJ, He JG, Nan JL, Guo YL, Xiong CM. Atorvastatin decreases C-reactive protein-induced inflammatoryresponse in pulmonary artery smooth muscle cells by inhibiting nuclear factor-kappaB pathway. Cardiovasc Ther. Spring2010;28(1):8-14.
Girgis RE, Mozammel S, Champion HC, et al. Regression of chronic hypoxic pulmonary hypertension by simvastatin.Am J Physiol Lung Cell Mol Physiol. May2007;292(5):L1105-1110.
4Zhang B, Shen M, Xu M, et al. Role of macrophage migration inhibitory factor in the proliferation of smooth musclecell in pulmonary hypertension. Mediators Inflamm.2012;2012:840737.
5Zhang Y, Talwar A, Tsang D, et al. Macrophage migration inhibitory factor mediates hypoxia-induced pulmonaryhypertension. Mol Med.2012;18:215-223.
6Chen D, Fang F, Yang Y, et al. Brahma-related gene1(Brg1) epigenetically regulates CAM activation during hypoxicpulmonary hypertension. Cardiovasc Res. Dec12013;100(3):363-373.
Yuan Z, Chen J, Chen D, et al. Megakaryocytic Leukemia1(MKL1) Regulates Hypoxia Induced PulmonaryHypertension in Rats. PLoS One.2014;9(3):e83895.
1Thangjam GS, Dimitropoulou C, Joshi AD, et al. Novel Mechanism of Attenuation of LPS-Induced NF-kB Activationby the hsp90Inhibitor,17-AAG, in Human Lung Microvascular Endothelial Cells. Am J Respir Cell Mol Biol. Dec42013.
2Ohata Y, Ogata S, Nakanishi K, et al. Proteomic analysis of the lung in rats with hypobaric hypoxia-induced pulmonaryhypertension. Histol Histopathol. Jul2013;28(7):893-902.
3Janssen LJ. Isoprostanes and lung vascular pathology. Am J Respir Cell Mol Biol. Oct2008;39(4):383-389.
4Hopkins N, McLoughlin P. The structural basis of pulmonary hypertension in chronic lung disease: remodelling,rarefaction or angiogenesis? J Anat. Oct2002;201(4):335-348.
Sarada S, Himadri P, Mishra C, Geetali P, Ram MS, Ilavazhagan G. Role of oxidative stress and NFkB inhypoxia-induced pulmonary edema. Exp Biol Med (Maywood). Sep2008;233(9):1088-1098.
6Doughan AK, Harrison DG, Dikalov SI. Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction:linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res. Feb292008;102(4):488-496.
7Fike CD, Dikalova A, Slaughter JC, Kaplowitz MR, Zhang Y, Aschner JL. Reactive oxygen species-reducing strategiesimprove pulmonary arterial responses to nitric oxide in piglets with chronic hypoxia-induced pulmonary hypertension.Antioxid Redox Signal. May102013;18(14):1727-1738.
8Fike CD, Aschner JL, Kaplowitz MR, Zhang Y, Madden JA. Reactive oxygen species scavengers improvevoltage-gated K(+) channel function in pulmonary arteries of newborn pigs with progressive hypoxia-induced pulmonaryhypertension. Pulm Circ. Sep2013;3(3):551-563.
1Zhou G, Dada LA, Wu M, et al. Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrialROS and hypoxia-inducible factor1. Am J Physiol Lung Cell Mol Physiol. Dec2009;297(6):L1120-1130.
2Wei HL, Zhang CY, Jin HF, Tang CS, Du JB. Hydrogen sulfide regulates lung tissue-oxidized glutathione and totalantioxidant capacity in hypoxic pulmonary hypertensive rats. Acta Pharmacol Sin. Jun2008;29(6):670-679.
3Yang Y, Zhang BK, Liu D, et al. Sodium hydrosulfide prevents hypoxia-induced pulmonary arterial hypertension inbroilers. British poultry science.2012;53(5):608-615.
4Villegas LR, Kluck D, Field C, et al. Superoxide dismutase mimetic, MnTE-2-PyP, attenuates chronic hypoxia-inducedpulmonary hypertension, pulmonary vascular remodeling, and activation of the NALP3inflammasome. Antioxid RedoxSignal. May102013;18(14):1753-1764.
5Chandel NS, Trzyna WC, McClintock DS, Schumacker PT. Role of oxidants in NF-kappa B activation and TNF-alphagene transcription induced by hypoxia and endotoxin. J Immunol. Jul152000;165(2):1013-1021.
6Klinke A, Moller A, Pekarova M, et al. Protective Effects of10-Nitro-Oleic Acid in a Hypoxia-Induced Murine Modelof Pulmonary Hypertension. Am J Respir Cell Mol Biol. Feb122014.
7Zhang B, Niu W, Xu D, et al. Oxymatrine prevents hypoxia-and monocrotaline-induced pulmonary hypertension inrats. Free Radic Biol Med. Jan152014.
Dorfmuller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J. Aug2003;22(2):358-363.
1Burke DL, Frid MG, Kunrath CL, et al. Sustained hypoxia promotes the development of a pulmonary artery-specificchronic inflammatory microenvironment. Am J Physiol Lung Cell Mol Physiol. Aug2009;297(2):L238-250.
2Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation.2004;109(2):159-165.
Bagnato A, Rosano L. Epithelial-mesenchymal transition in ovarian cancer progression: a crucial role for theendothelin axis. Cells Tissues Organs.2007;185(1-3):85-94.
4Masaki T. Historical review: Endothelin. Trends Pharmacol Sci. Apr2004;25(4):219-224.
5Li H, Chen SJ, Chen YF, et al. Enhanced endothelin-1and endothelin receptor gene expression in chronic hypoxia.Journal of applied physiology (Bethesda, Md.:1985). Sep1994;77(3):1451-1459.
6Van Hung T, Emoto N, Vignon-Zellweger N, et al. Inhibition of vascular endothelial growth factor receptor underhypoxia causes severe, human-like pulmonary arterial hypertension in mice: Potential roles of interleukin-6and
7endothelin. Life Sci. Jan82014.Rubens C, Ewert R, Halank M, et al. Big endothelin-1and endothelin-1plasma levels are correlated with the severityof primary pulmonary hypertension. Chest. Nov2001;120(5):1562-1569.
8Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1in pulmonary hypertension: marker ormediator of disease? Ann Intern Med. Mar151991;114(6):464-469.
9Yang Y, Chen D, Yuan Z, et al. Megakaryocytic leukemia1(MKL1) ties the epigenetic machinery to hypoxia-inducedtransactivation of endothelin-1. Nucleic Acids Res. Jul12013;41(12):6005-6017.
10Jain R, Shaul PW, Borok Z, Willis BC. Endothelin-1induces alveolar epithelial-mesenchymal transition throughendothelin type A receptor-mediated production of TGF-beta1. Am J Respir Cell Mol Biol. Jul2007;37(1):38-47.
Rosano L, Spinella F, Di Castro V, et al. Endothelin-1promotes epithelial-to-mesenchymal transition in humanovarian cancer cells. Cancer Res. Dec152005;65(24):11649-11657.
1Dias-Junior CA, Cau SB, Tanus-Santos JE.[Role of nitric oxide in the control of the pulmonary circulation:physiological, pathophysiological, and therapeutic implications]. J Bras Pneumol. Jun2008;34(6):412-419.
2李尚师,李素芝,郑必海,宋娟,李红,曲涛.:快速进入高原者血清NO及白介素-1,6,8含量变化观察.:中国煤炭工业医学杂志2007;10(9)1055-1056.
3Naeije R, Dedobbeleer C. Pulmonary hypertension and the right ventricle in hypoxia. Exp Physiol. Aug2013;98(8):1247-1256.
Yuan Z, Chen J, Chen D, et al. Megakaryocytic Leukemia1(MKL1) Regulates Hypoxia Induced PulmonaryHypertension in Rats. PLoS One.2014;9(3):e83895.
5Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. Oct1999;79(4):1283-1316.
6Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res. Sep162005;97(6):512-523.
7韩雅玲,肖艳平,齐岩梅,康建,徐凯,闫承慧.:胚胎血管发育早期PDGF-BB对血管平滑肌细胞趋化的影响.:中国病理生理杂志2008;24(2)251-256.
8Ciuclan L, Hussey MJ, Burton V, et al. Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathologyvia reduction in5-hydroxytryptamine through inhibition of tryptophan hydroxylase1expression. Am J Respir Crit CareMed. Jan12013;187(1):78-89.
9Merklinger SL, Jones PL, Martinez EC, Rabinovitch M. Epidermal growth factor receptor blockade mediates smoothmuscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation. Jul192005;112(3):423-431.
10Tuder RM, Cool CD, Yeager M, Taraseviciene-Stewart L, Bull TM, Voelkel NF. The pathobiology of pulmonaryhypertension. Endothelium. Clin Chest Med. Sep2001;22(3):405-418.
11Tamm M, Bihl M, Eickelberg O, Stulz P, Perruchoud AP, Roth M. Hypoxia-induced interleukin-6and interleukin-8production is mediated by platelet-activating factor and platelet-derived growth factor in primary human lung cells. Am JRespir Cell Mol Biol. Oct1998;19(4):653-661.
1Teyssier C, Le Romancer M, Sentis S, Jalaguier S, Corbo L, Cavailles V. Protein arginine methylation in estrogensignaling and estrogen-related cancers. Trends Endocrinol Metab. Mar2010;21(3):181-189.
2Wilkins MR, Wharton J, Grimminger F, Ghofrani HA. Phosphodiesterase inhibitors for the treatment of pulmonaryhypertension. Eur Respir J. Jul2008;32(1):198-209.
3Rashid M, Fahim M, Kotwani A. Efficacy of tadalafil in chronic hypobaric hypoxia-induced pulmonary hypertension:possible mechanisms. Fundamental&clinical pharmacology. Jun2013;27(3):271-278.
4Tsai BM, Turrentine MW, Sheridan BC, et al. Differential effects of phosphodiesterase-5inhibitors on hypoxicpulmonary vasoconstriction and pulmonary artery cytokine expression. Ann Thorac Surg. Jan2006;81(1):272-278.
5Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane andprostacyclin metabolites in pulmonary hypertension. N Engl J Med. Jul91992;327(2):70-75.
6Takemiya K, Kai H, Yasukawa H, Tahara N, Kato S, Imaizumi T. Mesenchymal stem cell-based prostacyclin synthasegene therapy for pulmonary hypertension rats. Basic Res Cardiol. May2010;105(3):409-417.
7高钰琪.高原军事医学.重庆出版社.2004.
1Bonnet S, Archer SL. Potassium channel diversity in the pulmonary arteries and pulmonary veins: implications forregulation of the pulmonary vasculature in health and during pulmonary hypertension. Pharmacol Ther. Jul2007;115(1):56-69.
2Yuan JX, Aldinger AM, Juhaszova M, et al. Dysfunctional voltage-gated K+channels in pulmonary artery smoothmuscle cells of patients with primary pulmonary hypertension. Circulation. Oct61998;98(14):1400-1406.
3Dong L, Li Y, Hu H, et al. Potential therapeutic targets for hypoxia-induced pulmonary artery hypertension. J TranslMed. Feb82014;12(1):39.
Nitta CH, Osmond DA, Herbert LM, et al. Role of ASIC1in the development of chronic hypoxia-induced pulmonaryhypertension. Am J Physiol Heart Circ Physiol. Jan12014;306(1):H41-52.
1Cheever KH. An overview of pulmonary arterial hypertension: risks, pathogenesis, clinical manifestations, andmanagement. J Cardiovasc Nurs. Mar-Apr2005;20(2):108-116; quiz117-108.
2Crosswhite P, Sun Z. Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension. J Hypertens.Feb2010;28(2):201-212.
3Wang Y, Wysocka J, Sayegh J, et al. Human PAD4regulates histone arginine methylation levels via demethylimination.Science.2004;306(5694):279-283.
van Dijk TB, Gillemans N, Stein C, et al. Friend of Prmt1, a novel chromatin target of protein argininemethyltransferases. Mol Cell Biol. Jan2010;30(1):260-272.
5Huang X, Fan R, Lu Y, et al. Regulatory effect of AMP-activated protein kinase on pulmonary hypertension induced bychronic hypoxia in rats: in vivo and in vitro studies. Mol Biol Rep. Feb252014.
6Shimizu T, Fukumoto Y, Tanaka S, Satoh K, Ikeda S, Shimokawa H. Crucial role of ROCK2in vascular smooth musclecells for hypoxia-induced pulmonary hypertension in mice. Arterioscler Thromb Vasc Biol. Dec2013;33(12):2780-2791.
7Malczyk M, Veith C, Fuchs B, et al. Classical transient receptor potential channel1in hypoxia-induced pulmonaryhypertension. Am J Respir Crit Care Med. Dec152013;188(12):1451-1459.
Horita H, Furgeson SB, Ostriker A, et al. Selective inactivation of PTEN in smooth muscle cells synergizes withhypoxia to induce severe pulmonary hypertension. Journal of the American Heart Association. Jun2013;2(3):e000188.
1Horita H, Furgeson SB, Ostriker A, et al. Selective inactivation of PTEN in smooth muscle cells synergizes withhypoxia to induce severe pulmonary hypertension. Journal of the American Heart Association. Jun2013;2(3):e000188.
2Nie X, Shi Y, Yu W, Xu J, Hu X, Du Y. Phosphorylation of PTEN increase in pathological right ventricular hypertrophyin rats with chronic hypoxia induced pulmonary hypertension. Chin Med J (Engl).2014;127(2):338-342.
3x Yi ES, Kim H, Ahn H, et al. Distribution of obstructive intimal lesions and their cellular phenotypes in chronicpulmonary hypertension. A morphometric and immunohistochemical study. Am J Respir Crit Care Med. Oct2000;162(4Pt1):1577-1586.
4Frid MG, Brunetti JA, Burke DL, et al. Hypoxia-induced pulmonary vascular remodeling requires recruitment ofcirculating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol. Feb2006;168(2):659-669.
5Stenmark KR, Davie N, Frid M, Gerasimovskaya E, Das M. Role of the adventitia in pulmonary vascular remodeling.Physiology (Bethesda). Apr2006;21:134-145.
6Quinn AM, Bedford MT, Espejo A, et al. A homogeneous method for investigation of methylation-dependentprotein-protein interactions in epigenetics. Nucleic Acids Res. Jan2010;38(2):e11.
7Morrell NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am CollCardiol. Jun302009;54(1Suppl):S20-31.
8Li XW, Du J, Hu GY, et al. Fluorofenidone attenuates vascular remodeling in hypoxia-induced pulmonary hypertensionof rats. Can J Physiol Pharmacol. Jan2014;92(1):58-69.
9Goumans MJ, Liu Z, ten Dijke P. TGF-beta signaling in vascular biology and dysfunction. Cell Res. Jan2009;19(1):116-127.
10Zhu PC, Huang L, Ge XN, Yan F, Wu RL, Ao QL. Transdifferentiation of pulmonary arteriolar endothelial cells intosmooth muscle-like cells regulated by myocardin involved in hypoxia-induced pulmonary vascular remodelling.International Journal of Experimental Pathology. Dec2006;87(6):463-474.
11Carvajal G, Rodriguez-Vita J, Rodrigues-Diez R, et al. Angiotensin II activates the Smad pathway during epithelialmesenchymal transdifferentiation. Kidney Int. Sep2008;74(5):585-595.
Wolf G. Renal injury due to renin-angiotensin-aldosterone system activation of the transforming growth factor-betapathway. Kidney Int. Dec2006;70(11):1914-1919.
1High FA, Zhang M, Proweller A, et al. An essential role for Notch in neural crest during cardiovascular developmentand smooth muscle differentiation. J Clin Invest. Feb2007;117(2):353-363.
2Morrow D, Guha S, Sweeney C, et al. Notch and vascular smooth muscle cell phenotype. Circ Res. Dec52008;103(12):1370-1382.
3Doi H, Iso T, Sato H, et al. Jagged1-selective notch signaling induces smooth muscle differentiation via aRBP-Jkappa-dependent pathway. J Biol Chem. Sep292006;281(39):28555-28564.
4Noseda M, McLean G, Niessen K, et al. Notch activation results in phenotypic and functional changes consistent withendothelial-to-mesenchymal transformation. Circ Res. Apr162004;94(7):910-917.
5Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol. Apr2000;109(1):235-242.
6Silva GV, Litovsky S, Assad JA, et al. Mesenchymal stem cells differentiate into an endothelial phenotype, enhancevascular density, and improve heart function in a canine chronic ischemia model. Circulation. Jan182005;111(2):150-156.
7Nikolova-Krstevski V, Bhasin M, Otu HH, Libermann T, Oettgen P. Gene expression analysis of embryonic stem cellsexpressing VE-cadherin (CD144) during endothelial differentiation. BMC Genomics.2008;9:240.
8Abedin M, Tintut Y, Demer LL. Mesenchymal stem cells and the artery wall. Circ Res. Oct12004;95(7):671-676.
9Hamano K, Li TS.[Cell-based therapeutic angiogenesis for the treatment of ischemic disease]. Nippon Geka GakkaiZasshi. Aug2004;105(8):464-468.
10Fuchs S, Baffour R, Zhou YF, et al. Transendocardial delivery of autologous bone marrow enhances collateralperfusion and regional function in pigs with chronic experimental myocardial ischemia. J Am Coll Cardiol. May2001;37(6):1726-1732.
1Ball MK, Waypa GB, Mungai PT, et al. Regulation of Hypoxia-induced Pulmonary Hypertension by Vascular SmoothMuscle Hypoxia-Inducible Factor-1alpha. Am J Respir Crit Care Med. Feb12014;189(3):314-324.
2Yan J, Shen Y, Wang Y, Li BB. Increased expression of hypoxia-inducible factor-1alpha in proliferating neointimallesions in a rat model of pulmonary arterial hypertension. Am J Med Sci. Feb2013;345(2):121-128.
3Shan F, Li J, Huang QY. HIF-1Alpha-Induced Up-Regulation of miR-9Contributes to Phenotypic Modulation inPulmonary Artery Smooth Muscle Cells During Hypoxia. J Cell Physiol. Feb252014.
4Kim SY, Choi YJ, Joung SM, Lee BH, Jung YS, Lee JY. Hypoxic stress up-regulates the expression of Toll-likereceptor4in macrophages via hypoxia-inducible factor. Immunology. Apr2010;129(4):516-524.
Zimnicka AM, Tang H, Guo Q, et al. Upregulated copper transporters in hypoxia-induced pulmonary hypertension.PLoS One.2014;9(3):e90544.
6Yue J, Guan J, Wang X, et al. MicroRNA-206is involved in hypoxia-induced pulmonary hypertension throughtargeting of the HIF-1alpha/Fhl-1pathway. Lab Invest. Jul2013;93(7):748-759.
7Hansmann G, Wagner RA, Schellong S, et al. Pulmonary arterial hypertension is linked to insulin resistance andreversed by peroxisome proliferator-activated receptor-gamma activation. Circulation. Mar132007;115(10):1275-1284.
8Rabinovitch M. PPARgamma and the pathobiology of pulmonary arterial hypertension. Adv Exp Med Biol.2010;661:447-458.
Li M, Li Z, Sun X, et al. Heme oxygenase-1/p21WAF1mediates peroxisome proliferator-activated receptor-gammasignaling inhibition of proliferation of rat pulmonary artery smooth muscle cells. FEBS J. Mar2010;277(6):1543-1550.
[1]高钰琪.高原军事医学.重庆：重庆出版社.2004
[2] Yidiz P. Molecular mechanisms of pulmonary hypertension. Clinica Chimica Acta.May2009;403(1-2):9-16.
[3] Ward JP, McMurtry IF. Mechanisms of hypoxic pulmonary vasoconstriction andtheir roles in pulmonary hypertension: new findings for an old problem. Curr OpinPharmacol. Jun2009;9(3):287-296.
[4] Rabinovitch M, Bothwell T, Hayakawa BN, Williams WG, Trusler GA, Rowe RD,Olley PM, Cutz E: Pulmonary artery endothelial abnormalities in patients withcongenital heart defects and pulmonary hypertension. A correlation of light withscanning electron microscopy and transmission electron microscopy. Lab Invest1986,55(6):632-653.
[5]陈小容,邹霞英:缺氧性肺动脉高压大鼠肺血管内皮细胞的变化.中国病理生理杂志1996,12(6):608-611.
[6] Botto L, Beretta E, Daffara R, Miserocchi G, Palestini P: Biochemical andmorphological changes in endothelial cells in response to hypoxic interstitial edema.Respir Res2006,7:7.
[7] Bagnato A, Rosano L. Epithelial-mesenchymal transition in ovarian cancerprogression: a crucial role for the endothelin axis. Cells Tissues Organs.2007;185(1-3):85-94.
[8] Li H, Chen SJ, Chen YF, et al. Enhanced endothelin-1and endothelin receptor geneexpression in chronic hypoxia. Journal of applied physiology (Bethesda, Md.:1985).Sep1994;77(3):1451-1459.
[9] Rubens C, Ewert R, Halank M, et al. Big endothelin-1and endothelin-1plasmalevels are correlated with the severity of primary pulmonary hypertension. Chest.Nov2001;120(5):1562-1569.
[10] Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1inpulmonary hypertension: marker or mediator of disease? Ann Intern Med. Mar151991;114(6):464-469.
[11] Yamashita K, Discher DJ, Hu J, Bishopric NH, Webster KA: Molecular regulation ofthe endothelin-1gene by hypoxia. Contributions of hypoxia-inducible factor-1,activator protein-1, GATA-2, AND p300/CBP. J Biol Chem2001,276(16):12645-12653.
[12] Yang Y, Chen D, Yuan Z, et al. Megakaryocytic leukemia1(MKL1) ties theepigenetic machinery to hypoxia-induced transactivation of endothelin-1. NucleicAcids Res. Jul12013;41(12):6005-6017.
[13] Savale L, Tu L, Rideau D, Izziki M, Maitre B, Adnot S, Eddahibi S: Impact ofinterleukin-6on hypoxia-induced pulmonary hypertension and lung inflammation inmice. Respir Res2009,10:6.
[14] Burke DL, Frid MG, Kunrath CL, Karoor V, Anwar A, Wagner BD, Strassheim D,Stenmark KR: Sustained hypoxia promotes the development of a pulmonaryartery-specific chronic inflammatory microenvironment. Am J Physiol Lung CellMol Physiol2009,297(2):L238-250.
[15] Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB:Interleukin-6overexpression induces pulmonary hypertension. Circ Res2009,104(2):236-244,228p following244.
[16] Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT,Roedersheimer MT, van Rooijen N, Stenmark KR: Hypoxia-induced pulmonaryvascular remodeling requires recruitment of circulating mesenchymal precursors of amonocyte/macrophage lineage. Am J Pathol2006,168(2):659-669.
[17] Barreiro O, Martin P, Gonzalez-Amaro R, Sanchez-Madrid F: Molecular cuesguiding inflammatory responses. Cardiovasc Res2010,86(2):174-182.
[18] He P: Leucocyte/endothelium interactions and microvessel permeability: coupled oruncoupled? Cardiovasc Res2010,87(2):281-290.
[19] Winning S, Splettstoesser F, Fandrey J, Frede S: Acute hypoxia inducesHIF-independent monocyte adhesion to endothelial cells through increasedintercellular adhesion molecule-1expression: the role of hypoxic inhibition of prolylhydroxylase activity for the induction of NF-kappa B. J Immunol2010,185(3):1786-1793.
[20] Golembeski SM, West J, Tada Y, Fagan KA: Interleukin-6causes mild pulmonaryhypertension and augments hypoxia-induced pulmonary hypertension in mice. Chest2005,128(6Suppl):572S-573S.
[21] Csiszar A, Wang M, Lakatta EG, Ungvari Z: Inflammation and endothelialdysfunction during aging: role of NF-kappaB. Journal of applied physiology(Bethesda, Md:1985)2008,105(4):1333-1341.
[22] Culver C, Sundqvist A, Mudie S, Melvin A, Xirodimas D, Rocha S: Mechanism ofhypoxia-induced NF-kappaB. Mol Cell Biol2010,30(20):4901-4921.
[23] Tong Q, Zheng L, Lin L, Li B, Wang D, Li D: Hypoxia-induced mitogenic factorpromotes vascular sion molecule-1expression via the PI-3K/Akt-NF-kappaBsignaling pathway. Am J Respir Cell Mol Biol6,35(4):444-456.
[24] Hargreaves DC, Crabtree GR: ATP-dependent chromatin remodeling: genetics,genomics and mechanisms. Cell Res2011,21(3):396-420.
[25] Schnitzler G, Sif S, Kingston RE: Human SWI/SNF interconverts a nucleosomebetween its base state and a stable remodeled state. Cell1998,94(1):17-27.
[26] Takeuchi JK, Lou X, Alexander JM, Sugizaki H, Delgado-Olguin P, Holloway AK,Mori AD, Wylie JN, Munson C, Zhu Y et al: Chromatin remodelling complexdosage modulates transcription factor function in heart development. Nat Commun2011,2:187.
[27] Khavari PA, Peterson CL, Tamkun JW, Mendel DB, Crabtree GR: BRG1contains aconserved domain of the SWI2/SNF2family necessary for normal mitotic growthand transcription. Nature1993,366(6451):170-174.
[28] Reyes JC, Barra J, Muchardt C, Camus A, Babinet C, Yaniv M: Altered control ofcellular proliferation in the absence of mammalian brahma (SNF2alpha). EMBO J1998,17(23):6979-6991.
[29] Rodriguez-Nieto S, Sanchez-Cespedes M: BRG1and LKB1: tales of two tumorsuppressor genes on chromosome19p and lung cancer. Carcinogenesis2009,30(4):547-554.
[30] Trotter KW, Archer TK: Nuclear receptors and chromatin remodeling machinery.Mol Cell Endocrinol2007,265-266:162-167.
[31] Yoo AS, Crabtree GR: ATP-dependent chromatin remodeling in neural development.Curr Opin Neurobiol2009,19(2):120-126.
[32] Saladi SV, Keenen B, Marathe HG, Qi H, Chin KV, de la Serna IL: Modulation ofextracellular matrix/adhesion molecule expression by BRG1is associated withincreased melanoma invasiveness. Mol Cancer2010,9:280.
[33] Zhang L, Zhang Q, Jones K, Patel M, Gong F: The chromatin remodeling factorBRG1stimulates nucleotide excision repair by facilitating recruitment of XPC tosites of DNA damage. Cell Cycle2009,8(23):3953-3959.
[34] Dykhuizen EC, Hargreaves DC, Miller EL, Cui K, Korshunov A, Kool M, Pfister S,Cho YJ, Zhao K, Crabtree GR: BAF complexes facilitate decatenation of DNA bytopoisomerase IIalpha. Nature2013,497(7451):624-627.
[35] Kadam S, Emerson BM: Transcriptional specificity of human SWI/SNF BRG1andBRM chromatin remodeling complexes. Mol Cell2003,11(2):377-389.
[36] Naito M, Zager RA, Bomsztyk K: BRG1increases transcription of proinflammatorygenes in renal ischemia. J Am Soc Nephrol2009,20(8):1787-1796.
[37] Wang F, Zhang R, Beischlag TV, Muchardt C, Yaniv M, Hankinson O: Roles ofBrahma and Brahma/SWI2-related gene1in hypoxic induction of the erythropoietingene. J Biol Chem2004,279(45):46733-46741.
[38] Zhou J, Zhang M, Fang H, El-Mounayri O, Rodenberg JM, Imbalzano AN, HerringBP: The SWI/SNF chromatin remodeling complex regulates myocardin-inducedsmooth muscle-specific gene expression. Arterioscler Thromb Vasc Biol2009,29(6):921-928.
[39] Limpert AS, Bai S, Narayan M, Wu J, Yoon SO, Carter BD, Lu QR: NF-kappaBForms a Complex with the Chromatin Remodeler BRG1to Regulate Schwann CellDifferentiation. J Neurosci2013,33(6):2388-2397.
[40] Zhang M, Fang H, Zhou J, Herring BP: A novel role of Brg1in the regulation ofSRF/MRTFA-dependent smooth muscle-specific gene expression. J Biol Chem2007,282(35):25708-25716.
[41] Sena JA, Wang L, Hu CJ. BRG1and BRM chromatin-remodeling complexesregulate the hypoxia response by acting as coactivators for a subset ofhypoxia-inducible transcription factor target genes. Mol Cell Biol. Oct2013;33(19):3849-3863.
[42] Fang F, Chen D, Yu L, Dai X, Yang Y, Tian W, Cheng X, Xu H, Weng X, Fang M etal: Proinflammatory stimuli engage Brahma related gene1and Brahma inendothelial injury. Circ Res2013,113(8):986-996.
[43] Mohrmann L, Verrijzer CP: Composition and functional specificity of SWI2/SNF2class chromatin remodeling complexes. Biochim Biophys Acta2005,1681(2-3):59-73.
[44] Trotter KW, Archer TK: The BRG1transcriptional coregulator. Nucl Recept Signal2008,6:e004.
[45] Phelan ML, Sif S, Narlikar GJ, Kingston RE: Reconstitution of a core chromatinremodeling complex from SWI/SNF subunits. Mol Cell1999,3(2):247-253.
[46] Hang CT, Yang J, Han P, Cheng HL, Shang C, Ashley E, Zhou B, Chang CP:Chromatin regulation by Brg1underlies heart muscle development and disease.Nature2010,466(7302):62-67.
[47] Jiang C, Liu F, Luo Y, Li P, Chen J, Xu G, Wang Y, Li X, Huang J, Gao Y: Geneexpression profiling of high altitude polycythemia in Han Chinese migrating to theQinghai-Tibetan plateau. Mol Med Rep2012,5(1):287-293.
[48] Ariumi Y, Serhan F, Turelli P, Telenti A, Trono D: The integrase interactor1(INI1)proteins facilitate Tat-mediated human immunodeficiency virus type1transcription.Retrovirology2006,3:47.
[49] Cao Y, Vo T, Millien G, Tagne JB, Kotton D, Mason RJ, Williams MC, Ramirez MI:Epigenetic mechanisms modulate thyroid transcription factor1-mediatedtranscription of the surfactant protein B gene. J Biol Chem2010,285(3):2152-2164.
[50] Coisy-Quivy M, Disson O, Roure V, Muchardt C, Blanchard JM, Dantonel JC: Rolefor Brm in cell growth control. Cancer Res2006,66(10):5069-5076.
[51] Zhang H, Gao Y, Zhao F, Dai Z, Meng T, Tu S, Yan Y: Hydrogen sulfide reducesmRNA and protein levels of beta-site amyloid precursor protein cleaving enzyme1in PC12cells. Neurochem Int2011,58(2):169-175.
[52] Hou X, Chen J, Luo Y, Liu F, Xu G, Gao Y. Silencing of STIM1attenuateshypoxia-induced PASMCs proliferation via inhibition of the SOC/Ca2+/NFATpathway. Respir Res.2013;14:2.
[53] Vachtenheim J, Ondrusova L, Borovansky J: SWI/SNF chromatin remodelingcomplex is critical for the expression of microphthalmia-associated transcriptionfactor in melanoma cells. Biochem Bioph Res Co2010,392(3):454-459.
[54] Miller SA, Mohn SE, Weinmann AS: Jmjd3and UTX play a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression. Mol Cell2010,40(4):594-605.
[55] Zhang HS, Gavin M, Dahiya A, Postigo AA, Ma D, Luo RX, Harbour JW, Dean DC:Exit from G1and S phase of the cell cycle is regulated by repressor complexescontaining HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell2000,101(1):79-89.
[56] Geiman TM, Sankpal UT, Robertson AK, Zhao Y, Zhao Y, Robertson KD: DNMT3Binteracts with hSNF2H chromatin remodeling enzyme, HDACs1and2, andcomponents of the histone methylation system. Biochem Biophys Res Commun2004,318(2):544-555.
[57] Sluiter W, Pietersma A, Lamers JM, Koster JF: Leukocyte adhesion molecules on thevascular endothelium: their role in the pathogenesis of cardiovascular disease and themechanisms underlying their expression. J Cardiovasc Pharmacol1993,22Suppl4:S37-44.
[58] de La Serna IL, Carlson KA, Hill DA, Guidi CJ, Stephenson RO, Sif S, Kingston RE,Imbalzano AN: Mammalian SWI-SNF complexes contribute to activation of thehsp70gene. Mol Cell Biol2000,20(8):2839-2851.
[59] Voraberger G, Schafer R, Stratowa C: Cloning of the human gene for intercellularadhesion molecule1and analysis of its5'-regulatory region. Induction by cytokinesand phorbol ester. J Immunol1991,147(8):2777-2786.
[60] Munoz C, Castellanos MC, Alfranca A, Vara A, Esteban MA, Redondo JM, deLandazuri MO: Transcriptional up-regulation of intracellular adhesion molecule-1inhuman endothelial cells by the antioxidant pyrrolidine dithiocarbamate involves theactivation of activating protein-1. J Immunol1996,157(8):3587-3597.
[61] Yu G, Rux AH, Ma P, Bdeir K, Sachais BS: Endothelial expression of E-selectin isinduced by the platelet-specific chemokine platelet factor4through LRP in anNF-kappaB-dependent manner. Blood2005,105(9):3545-3551.
[62] Jeong KW, Lee YH, Stallcup MR: Recruitment of the SWI/SNF chromatinremodeling complex to steroid hormone-regulated promoters by nuclear receptorcoactivator flightless-I. J Biol Chem2009,284(43):29298-29309.
[63] Treand C, du Chene I, Bres V, Kiernan R, Benarous R, Benkirane M, Emiliani S:Requirement for SWI/SNF chromatin-remodeling complex in Tat-mediatedactivation of the HIV-1promoter. EMBO J2006,25(8):1690-1699.
[64] Verma UN, Surabhi RM, Schmaltieg A, Becerra C, Gaynor RB: Small interferingRNAs directed against beta-catenin inhibit the in vitro and in vivo growth of coloncancer cells. Clin Cancer Res2003,9(4):1291-1300.
[65] Bito T, Roy S, Sen CK, Shirakawa T, Gotoh A, Ueda M, Ichihashi M, Packer L:Flavonoids differentially regulate IFN gamma-induced ICAM-1expression in humankeratinocytes: molecular mechanisms of action. FEBS Lett2002,520(1-3):145-152.
[66] Hattori Y, Suzuki K, Hattori S, Kasai K: Metformin inhibits cytokine-inducednuclear factor kappaB activation via AMP-activated protein kinase activation invascular endothelial cells. Hypertension2006,47(6):1183-1188.
[67] Fang F, Yang Y, Yuan Z, Gao Y, Zhou J, Chen Q, Xu Y: Myocardin-RelatedTranscription Factor A Mediates OxLDL-Induced Endothelial Injury. Circ Res2011.
[68] Ritchie MH, Fillmore RA, Lausch RN, Oakes JE: A role for NF-kappa B bindingmotifs in the differential induction of chemokine gene expression in human cornealepithelial cells. Invest Ophthalmol Vis Sci2004,45(7):2299-2305.
[69] Liu M, Kluger MS, D'Alessio A, Garcia-Cardena G, Pober JS: Regulation ofarterial-venous differences in tumor necrosis factor responsiveness of endothelialcells by anatomic context. Am J Pathol2008,172(4):1088-1099.
[70] Xu Y, Zhang J, Chen XB: The activity of p53is differentially regulated by Brm-andBrg1-containing SWI/SNF chromatin remodeling complexes. J Biol Chem2007,282(52):37429-37435.
[71] Halliday GM, Bock VL, Moloney FJ, Lyons JG: SWI/SNF: a chromatin-remodellingcomplex with a role in carcinogenesis. Int J Biochem Cell Biol2009,41(4):725-728.
[72] Monahan BJ, Villen J, Marguerat S, Bahler J, Gygi SP, Winston F: Fission yeastSWI/SNF and RSC complexes show compositional and functional differences frombudding yeast. Nat Struct Mol Biol2008,15(8):873-880.
[73] Zhang B, Chambers KJ, Faller DV, Wang S: Reprogramming of the SWI/SNFcomplex for co-activation or co-repression in prohibitin-mediated estrogen receptorregulation. Oncogene2007,26(50):7153-7157.
[74] Ramirez-Carrozzi VR, Nazarian AA, Li CC, Gore SL, Sridharan R, Imbalzano AN,Smale ST: Selective and antagonistic functions of SWI/SNF and Mi-2betanucleosome remodeling complexes during an inflammatory response. Genes Dev2006,20(3):282-296.
[75] Angelov D, Lenouvel F, Hans F, Muller CW, Bouvet P, Bednar J, Moudrianakis EN,Cadet J, Dimitrov S: The histone octamer is invisible when NF-kappaB binds to thenucleosome. J Biol Chem2004,279(41):42374-42382.
[76] Jenuwein T, Allis CD: Translating the histone code. Science2001,293(5532):1074-1080.
[77] Langleben D: Endothelin receptor antagonists in the treatment of pulmonary arterialhypertension. Clin Chest Med2007,28(1):117-125, viii.
[78] Goerre S, Wenk M, Bartsch P, Luscher TF, Niroomand F, Hohenhaus E, Oelz O,Reinhart WH: Endothelin-1in pulmonary hypertension associated with high-altitudeexposure. Circulation1995,91(2):359-364.
[79] Modesti PA, Vanni S, Morabito M, Modesti A, Marchetta M, Gamberi T, Sofi F,Savia G, Mancia G, Gensini GF et al: Role of endothelin-1in exposure to highaltitude: Acute Mountain Sickness and Endothelin-1(ACME-1) study. Circulation2006,114(13):1410-1416.
[80] Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S,Masaki T, Duguid WP, Stewart DJ: Expression of endothelin-1in the lungs ofpatients with pulmonary hypertension. N Engl J Med1993,328(24):1732-1739.
[81] Glenn DJ, Rahmutula D, Nishimoto M, Liang F, Gardner DG: Atrial natriureticpeptide suppresses endothelin gene expression and proliferation in cardiacfibroblasts through a GATA4-dependent mechanism. Cardiovasc Res2009,84(2):209-217.
[82] Mawji IA, Robb GB, Tai SC, Marsden PA: Role of the3'-untranslated region ofhuman endothelin-1in vascular endothelial cells. Contribution to transcript labilityand the cellular heat shock response. J Biol Chem2004,279(10):8655-8667.
[83] Budhiraja R, Tuder RM, Hassoun PM: Endothelial dysfunction in pulmonaryhypertension. Circulation2004,109(2):159-165.
[84] Yuan Z, Chen J, Chen D, Xu G, Xia M, Xu Y, Gao Y: Megakaryocytic Leukemia1(MKL1) Regulates Hypoxia Induced Pulmonary Hypertension in Rats. PLoS One2014,9(3):e83895.
[85] Zager RA, Johnson AC: Renal ischemia-reperfusion injury upregulates histone-modifying enzyme systems and alters histone expression at proinflammatory/profibrotic genes. Am J Physiol Renal Physiol2009,296(5): F1032-1041.
[86] Chen J, Tan B, Karteris E, Zervou S, Digby J, Hillhouse EW, Vatish M, Randeva HS:Secretion of adiponectin by human placenta: differential modulation of adiponectinand its receptors by cytokines. Diabetologia2006,49(6):1292-1302.
[87] Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A,Mirrakhimov MM, Aldashev A, Wilkins MR: Sildenafil inhibits hypoxia-inducedpulmonary hypertension. Circulation2001,104(4):424-428.
[88] Seldon MP, Silva G, Pejanovic N, Larsen R, Gregoire IP, Filipe J, Anrather J, SoaresMP: Heme oxygenase-1inhibits the expression of adhesion molecules associatedwith endothelial cell activation via inhibition of NF-kappaB RelA phosphorylation atserine276. J Immunol2007,179(11):7840-7851.
[89] Ren G, Zhao X, Zhang L, Zhang J, L'Huillier A, Ling W, Roberts AI, Le AD, Shi S,Shao C et al: Inflammatory cytokine-induced intercellular adhesion molecule-1andvascular cell adhesion molecule-1in mesenchymal stem cells are critical forimmunosuppression. J Immunol2010,184(5):2321-2328.
[90] Winkler F, Koedel U, Kastenbauer S, Pfister HW: Differential expression of nitricoxide synthases in bacterial meningitis: role of the inducible isoform for blood-brainbarrier breakdown. The Journal of infectious diseases2001,183(12):1749-1759.
[91] Mushaben EM, Hershey GK, Pauciulo MW, Nichols WC, Le Cras TD. Chronicallergic inflammation causes vascular remodeling and pulmonary hypertension inBMPR2hypomorph and wild-type mice. PLoS One.2012;7(3):e32468.
[92] Tabima DM, Hacker TA, Chesler NC: Measuring right ventricular function in thenormal and hypertensive mouse hearts using admittance-derived pressure-volumeloops. Am J Physiol Heart Circ Physiol2010,299(6):H2069-2075.
[93] Stenmark KR, Bouchey D, Nemenoff R, Dempsey EC, Das M: Hypoxia-inducedpulmonary vascular remodeling: contribution of the adventitial fibroblasts. PhysiolRes2000,49(5):503-517.
[94] Zhang B, Shen M, Xu M, Liu LL, Luo Y, Xu DQ, Wang YX, Liu ML, Liu Y, DongHY et al: Role of macrophage migration inhibitory factor in the proliferation ofsmooth muscle cell in pulmonary hypertension. Mediators Inflamm2012,2012:840737.
[95] Arnaud C, Beguin PC, Lantuejoul S, Pepin JL, Guillermet C, Pelli G, Burger F,Buatois V, Ribuot C, Baguet JP et al: The inflammatory preatheroscleroticremodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5inhibition. Am J Respir Crit Care Med2011,184(6):724-731.
[96] Weber C, Zernecke A, Libby P: The multifaceted contributions of leukocyte subsetsto atherosclerosis: lessons from mouse models. Nat Rev Immunol2008,8(10):802-815.
[97] Tian W, Xu H, Fang F, Chen Q, Xu Y, Shen A: Brahma-related gene1bridgesepigenetic regulation of proinflammatory cytokine production to steatohepatitis inmice. Hepatology2013,58(2):576-588.
[98] Glaros S, Cirrincione GM, Palanca A, Metzger D, Reisman D: Targeted knockout ofBRG1potentiates lung cancer development. Cancer Res2008,68(10):3689-3696.
[99] Reisman D, Glaros S, Thompson EA: The SWI/SNF complex and cancer. Oncogene2009,28(14):1653-1668.
[100] Ross S, Cheung E, Petrakis TG, Howell M, Kraus WL, Hill CS: Smads orchestratespecific histone modifications and chromatin remodeling to activate transcription.EMBO J2006,25(19):4490-4502
[1]高钰琪.高原军事医学.重庆出版社.2004.
[2] Sakao S, Tatsumi K. Vascular remodeling in pulmonary arterial hypertension:multiple cancer-like pathways and possible treatment modalities. Int J Cardiol. Feb172011;147(1):4-12.
[3] Jeffery TK, Wanstall JC. Pulmonary vascular remodeling: a target for therapeuticintervention in pulmonary hypertension. Pharmacol Ther. Oct2001;92(1):1-20.
[4] Mowen K, Tang J, Zhu W, et al. Arginine methylation of STAT1modulatesIFNalpha/beta-induced transcription. Cell.2001;104(5):731-741.
[5] Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growth factors, andpulmonary vascular remodeling. J Am Coll Cardiol. Jun302009;54(1Suppl):S10-19.
[6] Van Hung T, Emoto N, Vignon-Zellweger N, et al. Inhibition of vascular endothelialgrowth factor receptor under hypoxia causes severe, human-like pulmonary arterialhypertension in mice: Potential roles of interleukin-6and endothelin. Life Sci. Jan82014.
[7] Burke DL, Frid MG, Kunrath CL, et al. Sustained hypoxia promotes thedevelopment of a pulmonary artery-specific chronic inflammatorymicroenvironment. Am J Physiol Lung Cell Mol Physiol. Aug2009;297(2):L238-250.
[8] Tuder RM, Voelkel NF. Pulmonary hypertension and inflammation. Journal ofLaboratory and Clinical Medicine.1998;132(1):16-24.
[9] Humbert M, Monti G, Brenot F, et al. Increased interleukin-1and interleukin-6serum concentrations in severe primary pulmonary hypertension. Am J Respir CritCare Med. May1995;151(5):1628-1631.
[10] Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB.Interleukin-6overexpression induces pulmonary hypertension. Circ Res. Jan302009;104(2):236-244,228p following244.
[11]李尚师,李素芝,郑必海,宋娟,李红,曲涛.:快速进入高原者血清NO及白介素-1,6,8含量变化观察.:中国煤炭工业医学杂志2007;10(9)1055-1056.
[12] Matsuda N, Hattori Y. Systemic inflammatory response syndrome (SIRS): molecularpathophysiology and gene therapy. J Pharmacol Sci. Jul2006;101(3):189-198.
[13] Young KC, Hussein SM, Dadiz R, et al. Toll-like receptor4-deficient mice areresistant to chronic hypoxia-induced pulmonary hypertension. Exp Lung Res. Mar2010;36(2):111-119.
[14] Quarck R, Nawrot T, Meyns B, Delcroix M. C-reactive protein: a new predictor ofadverse outcome in pulmonary arterial hypertension. J Am Coll Cardiol. Apr72009;53(14):1211-1218.
[15] Li J, Li JJ, He JG, Nan JL, Guo YL, Xiong CM. Atorvastatin decreases C-reactiveprotein-induced inflammatory response in pulmonary artery smooth muscle cells byinhibiting nuclear factor-kappaB pathway. Cardiovasc Ther. Spring2010;28(1):8-14.
[16] Girgis RE, Mozammel S, Champion HC, et al. Regression of chronic hypoxicpulmonary hypertension by simvastatin. Am J Physiol Lung Cell Mol Physiol. May2007;292(5):L1105-1110.
[17] Zhang B, Shen M, Xu M, et al. Role of macrophage migration inhibitory factor inthe proliferation of smooth muscle cell in pulmonary hypertension. MediatorsInflamm.2012;2012:840737.
[18] Zhang Y, Talwar A, Tsang D, et al. Macrophage migration inhibitory factor mediateshypoxia-induced pulmonary hypertension. Mol Med.2012;18:215-223.
[19] Chen D, Fang F, Yang Y, et al. Brahma-related gene1(Brg1) epigeneticallyregulates CAM activation during hypoxic pulmonary hypertension. Cardiovasc Res.Dec12013;100(3):363-373.
[20] Yuan Z, Chen J, Chen D, et al. Megakaryocytic Leukemia1(MKL1) RegulatesHypoxia Induced Pulmonary Hypertension in Rats. PLoS One.2014;9(3):e83895.
[21] Thangjam GS, Dimitropoulou C, Joshi AD, et al. Novel Mechanism of Attenuationof LPS-Induced NF-kB Activation by the hsp90Inhibitor,17-AAG, in Human LungMicrovascular Endothelial Cells. Am J Respir Cell Mol Biol. Dec42013.
[22] Ohata Y, Ogata S, Nakanishi K, et al. Proteomic analysis of the lung in rats withhypobaric hypoxia-induced pulmonary hypertension. Histol Histopathol. Jul2013;28(7):893-902.
[23] Janssen LJ. Isoprostanes and lung vascular pathology. Am J Respir Cell Mol Biol.Oct2008;39(4):383-389.
[24] Hopkins N, McLoughlin P. The structural basis of pulmonary hypertension inchronic lung disease: remodelling, rarefaction or angiogenesis? J Anat. Oct2002;201(4):335-348.
[25] Sarada S, Himadri P, Mishra C, Geetali P, Ram MS, Ilavazhagan G. Role ofoxidative stress and NFkB in hypoxia-induced pulmonary edema. Exp Biol Med(Maywood). Sep2008;233(9):1088-1098.
[26] Doughan AK, Harrison DG, Dikalov SI. Molecular mechanisms of angiotensinII-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage andvascular endothelial dysfunction. Circ Res. Feb292008;102(4):488-496.
[27] Fike CD, Dikalova A, Slaughter JC, Kaplowitz MR, Zhang Y, Aschner JL. Reactiveoxygen species-reducing strategies improve pulmonary arterial responses to nitricoxide in piglets with chronic hypoxia-induced pulmonary hypertension. AntioxidRedox Signal. May102013;18(14):1727-1738.
[28] Fike CD, Aschner JL, Kaplowitz MR, Zhang Y, Madden JA. Reactive oxygenspecies scavengers improve voltage-gated K(+) channel function in pulmonaryarteries of newborn pigs with progressive hypoxia-induced pulmonary hypertension.Pulm Circ. Sep2013;3(3):551-563.
[29] Zhou G, Dada LA, Wu M, et al. Hypoxia-induced alveolar epithelial-mesenchymaltransition requires mitochondrial ROS and hypoxia-inducible factor1. Am J PhysiolLung Cell Mol Physiol. Dec2009;297(6):L1120-1130.
[30] Wei HL, Zhang CY, Jin HF, Tang CS, Du JB. Hydrogen sulfide regulates lungtissue-oxidized glutathione and total antioxidant capacity in hypoxic pulmonaryhypertensive rats. Acta Pharmacol Sin. Jun2008;29(6):670-679.
[31] Yang Y, Zhang BK, Liu D, et al. Sodium hydrosulfide prevents hypoxia-inducedpulmonary arterial hypertension in broilers. British poultry science.2012;53(5):608-615.
[32] Villegas LR, Kluck D, Field C, et al. Superoxide dismutase mimetic, MnTE-2-PyP,attenuates chronic hypoxia-induced pulmonary hypertension, pulmonary vascularremodeling, and activation of the NALP3inflammasome. Antioxid Redox Signal.May102013;18(14):1753-1764.
[33] Chandel NS, Trzyna WC, McClintock DS, Schumacker PT. Role of oxidants inNF-kappa B activation and TNF-alpha gene transcription induced by hypoxia andendotoxin. J Immunol. Jul152000;165(2):1013-1021.
[34] Klinke A, Moller A, Pekarova M, et al. Protective Effects of10-Nitro-Oleic Acid ina Hypoxia-Induced Murine Model of Pulmonary Hypertension. Am J Respir CellMol Biol. Feb122014.
[35] Zhang B, Niu W, Xu D, et al. Oxymatrine prevents hypoxia-andmonocrotaline-induced pulmonary hypertension in rats. Free Radic Biol Med. Jan152014.
[36] Dorfmuller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonaryarterial hypertension. Eur Respir J. Aug2003;22(2):358-363.
[37] Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonaryhypertension. Circulation.2004;109(2):159-165.
[38] Bagnato A, Rosano L. Epithelial-mesenchymal transition in ovarian cancerprogression: a crucial role for the endothelin axis. Cells Tissues Organs.2007;185(1-3):85-94.
[39] Masaki T. Historical review: Endothelin. Trends Pharmacol Sci. Apr2004;25(4):219-224.
[40] Li H, Chen SJ, Chen YF, et al. Enhanced endothelin-1and endothelin receptor geneexpression in chronic hypoxia. Journal of applied physiology (Bethesda, Md.:1985).Sep1994;77(3):1451-1459.
[41] Rubens C, Ewert R, Halank M, et al. Big endothelin-1and endothelin-1plasmalevels are correlated with the severity of primary pulmonary hypertension. Chest.Nov2001;120(5):1562-1569.
[42] Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1inpulmonary hypertension: marker or mediator of disease? Ann Intern Med. Mar151991;114(6):464-469.
[43] Yang Y, Chen D, Yuan Z, et al. Megakaryocytic leukemia1(MKL1) ties theepigenetic machinery to hypoxia-induced transactivation of endothelin-1. NucleicAcids Res. Jul12013;41(12):6005-6017.
[44] Jain R, Shaul PW, Borok Z, Willis BC. Endothelin-1induces alveolarepithelial-mesenchymal transition through endothelin type A receptor-mediatedproduction of TGF-beta1. Am J Respir Cell Mol Biol. Jul2007;37(1):38-47.
[45] Rosano L, Spinella F, Di Castro V, et al. Endothelin-1promotesepithelial-to-mesenchymal transition in human ovarian cancer cells. Cancer Res.Dec152005;65(24):11649-11657.
[46] Dias-Junior CA, Cau SB, Tanus-Santos JE.[Role of nitric oxide in the control of thepulmonary circulation: physiological, pathophysiological, and therapeuticimplications]. J Bras Pneumol. Jun2008;34(6):412-419.
[47] Naeije R, Dedobbeleer C. Pulmonary hypertension and the right ventricle in hypoxia.Exp Physiol. Aug2013;98(8):1247-1256.
[48] Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derivedgrowth factor. Physiol Rev. Oct1999;79(4):1283-1316.
[49] Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res.Sep162005;97(6):512-523.
[50]韩雅玲,肖艳平,齐岩梅,康建,徐凯,闫承慧.:胚胎血管发育早期PDGF-BB对血管平滑肌细胞趋化的影响.:中国病理生理杂志2008;24(2)251-256.
[51] Ciuclan L, Hussey MJ, Burton V, et al. Imatinib attenuates hypoxia-inducedpulmonary arterial hypertension pathology via reduction in5-hydroxytryptaminethrough inhibition of tryptophan hydroxylase1expression. Am J Respir Crit CareMed. Jan12013;187(1):78-89.
[52] Merklinger SL, Jones PL, Martinez EC, Rabinovitch M. Epidermal growth factorreceptor blockade mediates smooth muscle cell apoptosis and improves survival inrats with pulmonary hypertension. Circulation. Jul192005;112(3):423-431.
[53] Tuder RM, Cool CD, Yeager M, Taraseviciene-Stewart L, Bull TM, Voelkel NF. Thepathobiology of pulmonary hypertension. Endothelium. Clin Chest Med. Sep2001;22(3):405-418.
[54] Tamm M, Bihl M, Eickelberg O, Stulz P, Perruchoud AP, Roth M. Hypoxia-inducedinterleukin-6and interleukin-8production is mediated by platelet-activating factorand platelet-derived growth factor in primary human lung cells. Am J Respir CellMol Biol. Oct1998;19(4):653-661.
[55] Teyssier C, Le Romancer M, Sentis S, Jalaguier S, Corbo L, Cavailles V. Proteinarginine methylation in estrogen signaling and estrogen-related cancers. TrendsEndocrinol Metab. Mar2010;21(3):181-189.
[56] Wilkins MR, Wharton J, Grimminger F, Ghofrani HA. Phosphodiesterase inhibitorsfor the treatment of pulmonary hypertension. Eur Respir J. Jul2008;32(1):198-209.
[57] Rashid M, Fahim M, Kotwani A. Efficacy of tadalafil in chronic hypobarichypoxia-induced pulmonary hypertension: possible mechanisms. Fundamental&clinical pharmacology. Jun2013;27(3):271-278.
[58] Tsai BM, Turrentine MW, Sheridan BC, et al. Differential effects ofphosphodiesterase-5inhibitors on hypoxic pulmonary vasoconstriction andpulmonary artery cytokine expression. Ann Thorac Surg. Jan2006;81(1):272-278.
[59] Christman BW, McPherson CD, Newman JH, et al. An imbalance between theexcretion of thromboxane and prostacyclin metabolites in pulmonary hypertension.N Engl J Med. Jul91992;327(2):70-75.
[60] Takemiya K, Kai H, Yasukawa H, Tahara N, Kato S, Imaizumi T. Mesenchymalstem cell-based prostacyclin synthase gene therapy for pulmonary hypertension rats.Basic Res Cardiol. May2010;105(3):409-417.
[61] Bonnet S, Archer SL. Potassium channel diversity in the pulmonary arteries andpulmonary veins: implications for regulation of the pulmonary vasculature in healthand during pulmonary hypertension. Pharmacol Ther. Jul2007;115(1):56-69.
[62] Yuan JX, Aldinger AM, Juhaszova M, et al. Dysfunctional voltage-gated K+channels in pulmonary artery smooth muscle cells of patients with primarypulmonary hypertension. Circulation. Oct61998;98(14):1400-1406.
[63] Dong L, Li Y, Hu H, et al. Potential therapeutic targets for hypoxia-inducedpulmonary artery hypertension. J Transl Med. Feb82014;12(1):39.
[64] Nitta CH, Osmond DA, Herbert LM, et al. Role of ASIC1in the development ofchronic hypoxia-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol.Jan12014;306(1):H41-52.
[65] Cheever KH. An overview of pulmonary arterial hypertension: risks, pathogenesis,clinical manifestations, and management. J Cardiovasc Nurs. Mar-Apr2005;20(2):108-116; quiz117-108.
[66] Crosswhite P, Sun Z. Nitric oxide, oxidative stress and inflammation in pulmonaryarterial hypertension. J Hypertens. Feb2010;28(2):201-212.
[67] Wang Y, Wysocka J, Sayegh J, et al. Human PAD4regulates histone argininemethylation levels via demethylimination. Science.2004;306(5694):279-283.
[68] van Dijk TB, Gillemans N, Stein C, et al. Friend of Prmt1, a novel chromatin targetof protein arginine methyltransferases. Mol Cell Biol. Jan2010;30(1):260-272.
[69] Huang X, Fan R, Lu Y, et al. Regulatory effect of AMP-activated protein kinase onpulmonary hypertension induced by chronic hypoxia in rats: in vivo and in vitrostudies. Mol Biol Rep. Feb252014.
[70] Shimizu T, Fukumoto Y, Tanaka S, Satoh K, Ikeda S, Shimokawa H. Crucial role ofROCK2in vascular smooth muscle cells for hypoxia-induced pulmonaryhypertension in mice. Arterioscler Thromb Vasc Biol. Dec2013;33(12):2780-2791.
[71] Malczyk M, Veith C, Fuchs B, et al. Classical transient receptor potential channel1in hypoxia-induced pulmonary hypertension. Am J Respir Crit Care Med. Dec152013;188(12):1451-1459.
[72] Xu D, Niu W, Luo Y, et al. Endogenous estrogen attenuates hypoxia-inducedpulmonary hypertension by inhibiting pulmonary arterial vasoconstriction andpulmonary arterial smooth muscle cells proliferation. International journal ofmedical sciences.2013;10(6):771-781.
[73] Horita H, Furgeson SB, Ostriker A, et al. Selective inactivation of PTEN in smoothmuscle cells synergizes with hypoxia to induce severe pulmonary hypertension.Journal of the American Heart Association. Jun2013;2(3):e000188.
[74] Nie X, Shi Y, Yu W, Xu J, Hu X, Du Y. Phosphorylation of PTEN increase inpathological right ventricular hypertrophy in rats with chronic hypoxia inducedpulmonary hypertension. Chin Med J (Engl).2014;127(2):338-342.
[75] Yi ES, Kim H, Ahn H, et al. Distribution of obstructive intimal lesions and theircellular phenotypes in chronic pulmonary hypertension. A morphometric andimmunohistochemical study. Am J Respir Crit Care Med. Oct2000;162(4Pt1):1577-1586.
[76] Frid MG, Brunetti JA, Burke DL, et al. Hypoxia-induced pulmonary vascularremodeling requires recruitment of circulating mesenchymal precursors of amonocyte/macrophage lineage. Am J Pathol. Feb2006;168(2):659-669.
[77] Stenmark KR, Davie N, Frid M, Gerasimovskaya E, Das M. Role of the adventitia inpulmonary vascular remodeling. Physiology (Bethesda). Apr2006;21:134-145.
[78] Quinn AM, Bedford MT, Espejo A, et al. A homogeneous method for investigationof methylation-dependent protein-protein interactions in epigenetics. Nucleic AcidsRes. Jan2010;38(2):e11.
[79] Morrell NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonaryarterial hypertension. J Am Coll Cardiol. Jun302009;54(1Suppl):S20-31.
[80] Li XW, Du J, Hu GY, et al. Fluorofenidone attenuates vascular remodeling inhypoxia-induced pulmonary hypertension of rats. Can J Physiol Pharmacol. Jan2014;92(1):58-69.
[81] Goumans MJ, Liu Z, ten Dijke P. TGF-beta signaling in vascular biology anddysfunction. Cell Res. Jan2009;19(1):116-127.
[82] Zhu PC, Huang L, Ge XN, Yan F, Wu RL, Ao QL. Transdifferentiation of pulmonaryarteriolar endothelial cells into smooth muscle-like cells regulated by myocardininvolved in hypoxia-induced pulmonary vascular remodelling. International Journalof Experimental Pathology. Dec2006;87(6):463-474.
[83] Carvajal G, Rodriguez-Vita J, Rodrigues-Diez R, et al. Angiotensin II activates theSmad pathway during epithelial mesenchymal transdifferentiation. Kidney Int. Sep2008;74(5):585-595.
[84] Wolf G. Renal injury due to renin-angiotensin-aldosterone system activation of thetransforming growth factor-beta pathway. Kidney Int. Dec2006;70(11):1914-1919.
[85] High FA, Zhang M, Proweller A, et al. An essential role for Notch in neural crestduring cardiovascular development and smooth muscle differentiation. J Clin Invest.Feb2007;117(2):353-363.
[86] Morrow D, Guha S, Sweeney C, et al. Notch and vascular smooth muscle cellphenotype. Circ Res. Dec52008;103(12):1370-1382.
[87] Doi H, Iso T, Sato H, et al. Jagged1-selective notch signaling induces smoothmuscle differentiation via a RBP-Jkappa-dependent pathway. J Biol Chem. Sep292006;281(39):28555-28564.
[88] Noseda M, McLean G, Niessen K, et al. Notch activation results in phenotypic andfunctional changes consistent with endothelial-to-mesenchymal transformation. CircRes. Apr162004;94(7):910-917.
[89] Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilicalcord blood. Br J Haematol. Apr2000;109(1):235-242.
[90] Silva GV, Litovsky S, Assad JA, et al. Mesenchymal stem cells differentiate into anendothelial phenotype, enhance vascular density, and improve heart function in acanine chronic ischemia model. Circulation. Jan182005;111(2):150-156.
[91] Nikolova-Krstevski V, Bhasin M, Otu HH, Libermann T, Oettgen P. Gene expressionanalysis of embryonic stem cells expressing VE-cadherin (CD144) duringendothelial differentiation. BMC Genomics.2008;9:240.
[92] Abedin M, Tintut Y, Demer LL. Mesenchymal stem cells and the artery wall. CircRes. Oct12004;95(7):671-676.
[93] Hamano K, Li TS.[Cell-based therapeutic angiogenesis for the treatment ofischemic disease]. Nippon Geka Gakkai Zasshi. Aug2004;105(8):464-468.
[94] Fuchs S, Baffour R, Zhou YF, et al. Transendocardial delivery of autologous bonemarrow enhances collateral perfusion and regional function in pigs with chronicexperimental myocardial ischemia. J Am Coll Cardiol. May2001;37(6):1726-1732.
[95] Ball MK, Waypa GB, Mungai PT, et al. Regulation of Hypoxia-induced PulmonaryHypertension by Vascular Smooth Muscle Hypoxia-Inducible Factor-1alpha. Am JRespir Crit Care Med. Feb12014;189(3):314-324.
[96] Yan J, Shen Y, Wang Y, Li BB. Increased expression of hypoxia-induciblefactor-1alpha in proliferating neointimal lesions in a rat model of pulmonary arterialhypertension. Am J Med Sci. Feb2013;345(2):121-128.
[97] Shan F, Li J, Huang QY. HIF-1Alpha-Induced Up-Regulation of miR-9Contributesto Phenotypic Modulation in Pulmonary Artery Smooth Muscle Cells DuringHypoxia. J Cell Physiol. Feb252014.
[98] Kim SY, Choi YJ, Joung SM, Lee BH, Jung YS, Lee JY. Hypoxic stress up-regulatesthe expression of Toll-like receptor4in macrophages via hypoxia-inducible factor.Immunology. Apr2010;129(4):516-524.
[99] Zimnicka AM, Tang H, Guo Q, et al. Upregulated copper transporters inhypoxia-induced pulmonary hypertension. PLoS One.2014;9(3):e90544.
[100] Yue J, Guan J, Wang X, et al. MicroRNA-206is involved in hypoxia-inducedpulmonary hypertension through targeting of the HIF-1alpha/Fhl-1pathway. LabInvest. Jul2013;93(7):748-759.
[101] Hansmann G, Wagner RA, Schellong S, et al. Pulmonary arterial hypertension islinked to insulin resistance and reversed by peroxisome proliferator-activatedreceptor-gamma activation. Circulation. Mar132007;115(10):1275-1284.
[102] Rabinovitch M. PPARgamma and the pathobiology of pulmonary arterialhypertension. Adv Exp Med Biol.2010;661:447-458.
[103] Li M, Li Z, Sun X, et al. Heme oxygenase-1/p21WAF1mediates peroxisomeproliferator-activated receptor-gamma signaling inhibition of proliferation of ratpulmonary artery smooth muscle cells. FEBS J. Mar2010;277(6):1543-1550.