SIRT1在肺动脉高压血管重塑中的作用和机制研究
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摘要
背景：肺动脉高压是一种不同病因所致肺动脉阻塞,进而引起肺血管阻力增加,最终导致右心衰竭的临床综合征,其进展迅速,预后甚差。现有治疗手段很难阻止更无法逆转疾病的进展,因此PAH目前仍然无法治愈。肺血管重塑是肺动脉高压的显著病理学改变,肺动脉平滑肌增殖是肺血管重塑的关键所在,亦是阻止和逆转PAH进程的关键所在。目前对肺血管重塑发生、发展过程中肺动脉平滑肌增殖所涉及的分子事件还知晓甚少。
目的：研究Ⅲ类去乙酰化酶SIRT1对肺动脉平滑肌增殖,肺血管重塑的影响。
方法：首先选用人肺动脉平滑肌细胞(HPASMCs)作为研究对象,首先应用realtimePCR和western blot检测了PDGF-BB诱导时HPASMCs中SIRT1的表达变化；进一步流式细胞术检测JSIRT1在体外对细胞周期的影响；随后过表达和干扰SIRT1,通过realtime PCR和western blot观察基础水平和PDGF-BB诱导后SIRT1对细胞周期蛋白,K+通道蛋白表达水平的影响。其次,建立野百合碱(MCT)诱导的大鼠PAH模型,用SIRT1的激活剂resveratrol进行干预,用漂浮导管检测大鼠肺动脉压力；采用HE染色、免疫组化、EVG染色、TUNEL染色等方法观察模型鼠中膜增厚,血管平滑肌细胞增殖,动脉中凋亡细胞数；通过realtime PCR和western blot观察PAH大鼠肺组织中SIRT1,细胞周期蛋白,K+通道蛋白等的表达变化以及resveratrol干预后这些分子的表达变化。
结果：PDGF-BB刺激引起HPASMCs中SIRT1的mRNA和蛋白水平出现先降低后增加的动态改变。过表达SIRT1可以将PDGF-BB诱导的HPASMCS阻滞在G1期。过表达SIRT1抑制PDGF-BB诱导的HPASMCs中Kvl.5和Kv2.1的mRNA水平的下调。过表达SlRT1下调HPASMCs中周期蛋白CyclinDl, CyclinE, CDK2的表达,上调p21的表达；SIRT1RNAi上调HPASMCs中CyclinDl, CyclinE, CDK2的表达,下调p21的表达。Resveratrol下调CyclinDl, CyclinE, CDK2的表达,上调p21的表达,SIRT1介导了resveratrol的这种作用。MCT诱导的PAH大鼠肺组织中SIRT1、Kvl.5和Kv2.1,p21的表达明显降低,resveratrol干预减少SIRT1、Kvl.5和Kv2.1,p21的降低,同时改善了肺小动脉中膜增厚、非肌性动脉的肌化,降低了肺动脉压力。
结论：在细胞水平,PDGF-BB增力HPASMCs中细胞周期蛋白CyclinDl, CyclinE, CDK2的表达,降低p21、Kv1.5和Kv2.1的表达。SIRT1可以下调CyclinDl, CyclinE, CDK2的表达,上调p21、Kv1.5和Kv2.1的表达。将HPASMCs阻滞在Gl期,抑制HPASMCs增殖。SIRT1介导了resveratrol对细胞周期蛋白CyclinD1、CyclinE、 CDK2、p21的调控。在动物水平,resveratrol能增加MCT诱导的PAH大鼠肺组织SIRT1、Kv1.5、Kv2.1和p21的表达,抑制PAH的发展。
Rationale:Pulmonary arterial hypertension (PAH) is a heterogenous syndrome in which pulmonary arterial obstruction increases pulmonary vascular resistance, which leads to right ventricular (RV) failure. Despite aggressive treatments, the mortality of PAH remains high. Current therapies can hardly prevent from progression of PAH. Vascular remodeling is the key pathology of PAH. Proliferation of pulmonary arterial smooth muscle cells (PASMC) is the cytological basis of vascular remodeling. Inhibition of PASMC proliferation might contribute to the regression of PAH.
Objective:To investigate the role of SIRT1, a class Ⅲ histone deacetylase, in the regulation of human pulmonary arterial smooth muscle cells (HPASMCs) proliferation and vascular remodeling in monocrotaline induced PAH rats.
Methods:With realtime-PCR and western blot, we examined the expression of SIRT1in HPASMCs stimulated with PDGF-BB. FCM was applied to detect the effects of SIRT1on HPASMCs proliferation in vitro. After over-expression of RNAi to SIRT1, expression of cell cycle protein which functions in G1state, potassium channels proteins including Kv1.5and Kv2.1were examined by western blot or realtime-PCR. Furthermore, rats were injected with monocrotaline (MCT) to developed pulmonary arterial hypertension and resveratrol (2.5mg/kg per day or20mg/kg per day) was feeded orally. We investigated the efficacy of resveratrol to prevent from developing pulmonary arterial hypertension by hemodynamics, HE staining, immunohistochemistry, EVG staining and TUNEL assay. At last,the expressions of SIRT1, Kv1.5, Kv2.1and p21in the lungs of rats were detected by realtime-PCR or western blot.
Results:We found that the expression of SIRT1in HPASMCs decreased after PDGF-BB stimulation. Adenoviral overexpression of SIRT1inhibited HPASMCs proliferation and led to an arrest of the cells in phase G1. In addition, SIRT1decreased the expression of CyclinDl, CyclinE, CDK2, increased the expression of p21,the G1phase regulatory protein.Meanwhile, SIRT1increased the expression of Kv1.5and Kv2.1. Moreover, resveratraol, SIRT1angonist could attenuat MCT induced pulmonary arterial remodeling and increased SIRT1, Kvl.5, Kv2.1and p21in the lungs of rats, which lead to improvement of pulmonary arterial hypertension.
Conclusion:Our studies show that SIRT1decreases the expression of CyclinD1, CyclinE and CDK2, increases the expression of Kv1.5and Kv2.1, which result in inhibition of HPASMCs proliferation. Resveratraol, the angonist of SIRT1, exerts antiproliferative effects in the pulmonary arteries, which may contribute to the prevention of pulmonary arterial hypertension
目的：研究Ⅲ类去乙酰化酶SIRT1对肺动脉平滑肌增殖,肺血管重塑的影响。
方法：首先选用人肺动脉平滑肌细胞(HPASMCs)作为研究对象,首先应用realtimePCR和western blot检测了PDGF-BB诱导时HPASMCs中SIRT1的表达变化；进一步流式细胞术检测JSIRT1在体外对细胞周期的影响；随后过表达和干扰SIRT1,通过realtime PCR和western blot观察基础水平和PDGF-BB诱导后SIRT1对细胞周期蛋白,K+通道蛋白表达水平的影响。其次,建立野百合碱(MCT)诱导的大鼠PAH模型,用SIRT1的激活剂resveratrol进行干预,用漂浮导管检测大鼠肺动脉压力；采用HE染色、免疫组化、EVG染色、TUNEL染色等方法观察模型鼠中膜增厚,血管平滑肌细胞增殖,动脉中凋亡细胞数；通过realtime PCR和western blot观察PAH大鼠肺组织中SIRT1,细胞周期蛋白,K+通道蛋白等的表达变化以及resveratrol干预后这些分子的表达变化。
结果：PDGF-BB刺激引起HPASMCs中SIRT1的mRNA和蛋白水平出现先降低后增加的动态改变。过表达SIRT1可以将PDGF-BB诱导的HPASMCS阻滞在G1期。过表达SIRT1抑制PDGF-BB诱导的HPASMCs中Kvl.5和Kv2.1的mRNA水平的下调。过表达SlRT1下调HPASMCs中周期蛋白CyclinDl, CyclinE, CDK2的表达,上调p21的表达；SIRT1RNAi上调HPASMCs中CyclinDl, CyclinE, CDK2的表达,下调p21的表达。Resveratrol下调CyclinDl, CyclinE, CDK2的表达,上调p21的表达,SIRT1介导了resveratrol的这种作用。MCT诱导的PAH大鼠肺组织中SIRT1、Kvl.5和Kv2.1,p21的表达明显降低,resveratrol干预减少SIRT1、Kvl.5和Kv2.1,p21的降低,同时改善了肺小动脉中膜增厚、非肌性动脉的肌化,降低了肺动脉压力。
结论：在细胞水平,PDGF-BB增力HPASMCs中细胞周期蛋白CyclinDl, CyclinE, CDK2的表达,降低p21、Kv1.5和Kv2.1的表达。SIRT1可以下调CyclinDl, CyclinE, CDK2的表达,上调p21、Kv1.5和Kv2.1的表达。将HPASMCs阻滞在Gl期,抑制HPASMCs增殖。SIRT1介导了resveratrol对细胞周期蛋白CyclinD1、CyclinE、 CDK2、p21的调控。在动物水平,resveratrol能增加MCT诱导的PAH大鼠肺组织SIRT1、Kv1.5、Kv2.1和p21的表达,抑制PAH的发展。
Rationale:Pulmonary arterial hypertension (PAH) is a heterogenous syndrome in which pulmonary arterial obstruction increases pulmonary vascular resistance, which leads to right ventricular (RV) failure. Despite aggressive treatments, the mortality of PAH remains high. Current therapies can hardly prevent from progression of PAH. Vascular remodeling is the key pathology of PAH. Proliferation of pulmonary arterial smooth muscle cells (PASMC) is the cytological basis of vascular remodeling. Inhibition of PASMC proliferation might contribute to the regression of PAH.
Objective:To investigate the role of SIRT1, a class Ⅲ histone deacetylase, in the regulation of human pulmonary arterial smooth muscle cells (HPASMCs) proliferation and vascular remodeling in monocrotaline induced PAH rats.
Methods:With realtime-PCR and western blot, we examined the expression of SIRT1in HPASMCs stimulated with PDGF-BB. FCM was applied to detect the effects of SIRT1on HPASMCs proliferation in vitro. After over-expression of RNAi to SIRT1, expression of cell cycle protein which functions in G1state, potassium channels proteins including Kv1.5and Kv2.1were examined by western blot or realtime-PCR. Furthermore, rats were injected with monocrotaline (MCT) to developed pulmonary arterial hypertension and resveratrol (2.5mg/kg per day or20mg/kg per day) was feeded orally. We investigated the efficacy of resveratrol to prevent from developing pulmonary arterial hypertension by hemodynamics, HE staining, immunohistochemistry, EVG staining and TUNEL assay. At last,the expressions of SIRT1, Kv1.5, Kv2.1and p21in the lungs of rats were detected by realtime-PCR or western blot.
Results:We found that the expression of SIRT1in HPASMCs decreased after PDGF-BB stimulation. Adenoviral overexpression of SIRT1inhibited HPASMCs proliferation and led to an arrest of the cells in phase G1. In addition, SIRT1decreased the expression of CyclinDl, CyclinE, CDK2, increased the expression of p21,the G1phase regulatory protein.Meanwhile, SIRT1increased the expression of Kv1.5and Kv2.1. Moreover, resveratraol, SIRT1angonist could attenuat MCT induced pulmonary arterial remodeling and increased SIRT1, Kvl.5, Kv2.1and p21in the lungs of rats, which lead to improvement of pulmonary arterial hypertension.
Conclusion:Our studies show that SIRT1decreases the expression of CyclinD1, CyclinE and CDK2, increases the expression of Kv1.5and Kv2.1, which result in inhibition of HPASMCs proliferation. Resveratraol, the angonist of SIRT1, exerts antiproliferative effects in the pulmonary arteries, which may contribute to the prevention of pulmonary arterial hypertension
引文
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1. Thenappan T, Shah SJ, Rich S, et al. A USA-based registry for pulmonary arterial hypertension:1982-2006. Eur Respir J. Dec 2007;30(6):1103-1110.
2. Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. JAm Coll Cardiol. Jun 16 2004;43(12 Suppl S):13S-24S.
3. Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. JAm Coll Cardiol. Jun 16 2004;43(12 Suppl S):25S-32S.
4. Tuder RM, Chacon M, Alger L, et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension:evidence for a process of disordered angiogenesis. JPathol. Oct 2001;195(3):367-374.
5. Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. Jul 9 1992;327(2):70-75.
6. Steudel W, Ichinose F, Huang PL, et al. Pulmonary vasoconstriction and hypertension in mice with targeted disruption of the endothelial nitric oxide synthase (NOS 3) gene. Circ Res. Jul 1997;81(1):34-41.
7. Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension:marker or mediator of disease? Ann Intern Med. Mar 15 1991;114(6):464-469.
8.. Sakao S, Taraseviciene-Stewart L, Lee JD, et al. Initial apoptosis is followed by increased proliferation of apoptosis-resistant endothelial cells. Faseb J. Jul 2005;19(9):1178-1180.
9. McMurtry MS, Moudgil R, Hashimoto K, et al. Overexpression of human bone morphogenetic protein receptor 2 does not ameliorate monocrotaline pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol. Apr 2007;292(4):L872-878.
10. McMurtry MS, Archer SL, Altieri DC, et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest. Jun 2005;115(6):1479-1491.
11. Eddahibi S, Raffestin B, Hamon M, et al. Is the serotonin transporter involved in the pathogenesis of pulmonary hypertension? J Lab Clin Med. Apr 2002; 139(4):194-201.
12. Guignabert C, Izikki M, Tu LI, et al. Transgenic mice overexpressing the 5-hydroxytryptamine transporter gene in smooth muscle develop pulmonary hypertension. Circ Res. May 26 2006;98(10):1323-1330.
13. Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. Oct 2005;115(10):2811-2821.
14. Moreno-Vinasco L, Gomberg-Maitland M, Maitland ML, et al. Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiol Genomics. Apr 22 2008;33(2):278-291.
15. Yuan XJ, Wang J, Juhaszova M, et al. Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet. Mar 7 1998;351(9104):726-727.
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19. Bonnet S, Michelakis ED, Porter CJ, et al. An abnormal mitochondrial-hypoxia inducible factor-lalpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats:similarities to human pulmonary arterial hypertension. Circulation. Jun 6 2006;113(22):2630-2641.
20. Bonnet S, Archer SL, Allalunis-Turner J, et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. Jan 2007;11(1):37-51.
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