FIZZ1在动脉粥样硬化进展中的作用及其机制
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摘要
研究背景
动脉粥样硬化(atherosclerosis,AS)发病机制的研究已经经历了一个多世纪,主要围绕4种学说:脂肪浸润学说、血小板聚集和血栓形成学说、平滑肌细胞克隆学说和损伤反应学说,但至今详细发病机理仍未完全阐明。近年来不少研究发现,动脉粥样硬化的病理表现具有炎症病理的基本表现形式:变质、渗出和增生,其形成过程中也会出现类似类风湿性关节炎、慢性胰腺炎和肝硬化等慢性炎症性疾病的细胞间相互作用,随着炎症细胞和炎症介质的不断检出,动脉粥样硬化不再被认为是单纯的动脉壁脂质堆积的疾病,而是进展性炎症反应,符合炎症表现的普遍规律。目前,在动脉粥样硬化发现的促炎因子较多,如血小板源性生长因子β(PDGF-β)、血小板衍生因子(PDEF)、单核细胞趋化蛋白1、白细胞介素3、环氧合酶-2、基质金属蛋白酶、去组合蛋白、脂肪酸结合蛋白等,由于目前临床针对上述介质的抗动脉粥样硬化药物起效缓慢且疗效有待提高,因此是否还有其它炎症因子参与动脉粥样硬化进展有待进一步研究。FIZZ1(Found in Inflammatory Zone 1)是2000年新发现的一个与炎症相关的缺氧诱导有丝分裂因子,是运用表达序列标记数据库扫描的方法发现的一种分泌型蛋白,分子量9.4KD,具有刺激肺动脉平滑肌细胞增殖、收缩血管、促进血管新生、刺激肌纤维母细胞分化等功能,在脂肪组织的间质血管以及选择性激活的巨噬细胞中均有表达,缺氧的肺血管壁也有表达,在实验性肺纤维化、哮喘、过敏性肺炎、寄生虫感染等疾病中具有重要意义,其在动脉粥样硬化中是否表达则为未知,由于动脉粥样硬化斑块内存在Th2型细胞因子以及大量激活的巨噬细胞,动脉粥样硬化的血管壁也存在缺氧,因此,我们推测在动脉粥样硬化斑块内可能有FIZZ1表达。本实验用免疫组织化学方法检测动脉粥样硬化斑块内FIZZ1表达,RT-PCR检测FIZZ1mRNA表达,并探讨FIZZ1对体外培养的平滑肌细胞增殖,平滑肌细胞清道夫受体SR-A,巨噬细胞CD36表达影响,同时探讨降脂治疗对动脉粥样硬化斑块FIZZ1表达的影响。
研究方法
本研究分三部分,第一部分:选取C57BL/6J ApoE基因敲除鼠及C57BL/6J野生型小鼠,分别喂食高脂饲料及普通饲料,24周后处死小鼠,石蜡包埋血管后作连续切片,行HE染色及FIZZ1免疫组化染色,检测斑块FIZZ1表达情况, RT-PCR检测动脉粥样硬化斑块内FIZZ1mRNA表达,然后,模拟粥样斑块内细胞因子环境,用Th2型细胞因子刺激培养的平滑肌细胞以及巨噬细胞,RT-PCR以及激光共聚焦显微镜观察刺激后细胞FIZZ1mRNA及其蛋白表达情况,初步鉴定粥样斑块内分泌FIZZ1的可能的细胞;第二部分用终浓度分别为3×10~(-6)mmol/L,9×10~(-6)mmol/L,2.7×10~(-5)mmol/L的FIZZ1刺激培养的平滑肌细胞,3H掺入法以及MTT法测定FIZZ1对平滑肌细胞增殖的影响;用ox-LDL以及终浓度分别为3×10~(-6)mmol/L , 9×10~(-6)mmol/L , 2.7×10~(-5)mmol/L的FIZZ1刺激培养的平滑肌细胞,蛋白质印迹技术确认SR-A表达后,激光共聚焦显微镜对SR-A表达进行定位,用流式细胞术检测FIZZ1对平滑肌细胞SR-A及其巨噬细胞CD36表达的影响,评价FIZZ1能否影响动脉粥样硬化吞噬脂质的关键受体。第三部分:制作动脉粥样硬化以及高脂血症动物模型,然后用辛伐他汀干预实验动物,21周后,用免疫组化方法检测粥样斑块FIZZ1蛋白表达情况,RT-PCR方法检测FIZZ1mRNA表达情况,同时检测动脉粥样硬化斑块形态及其血脂水平,探讨调脂治疗对FIZZ1表达的影响。
结果
1.ApoE基因敲除鼠高脂饲养24周后,主动脉根部明显形成动脉粥样硬化,斑块体积大,免疫组化可见FIZZ1在动脉粥样硬化斑块内明显表达,RT-PCR可见FIZZ1mRNA表达,同龄野生型C57BL/6J鼠正常血管壁内,未见FIZZ1表达,Th2型细胞因子能刺激培养的巨噬细胞表达FIZZ1,但不能刺激体外培养的平滑肌细胞表达FIZZ1。
2.MTT检测平滑肌细胞增殖提示,FIZZ1 3×10~(-6)mmol/L组与对照组吸光度值比较,明显升高,P<0.05,差异有显著性;FIZZ1 9×10~(-6)mmol/L组与FIZZ1 3×10~(-6)mmol/L组比较,吸光度值明显升高,差异有显著性,P<0.05, FIZZ1 2.7×10~(-5)mmol/L组与9×10~(-6)mmol/L组比较,吸光度值明显升高,差异有显著性,说明FIZZ1能刺激平滑肌细胞增殖。3H-TdR掺入法检测也提示FIZZ1刺激平滑肌细胞增殖。
3.激光共聚焦显微镜可见在ox-LDL刺激24小时的平滑肌细胞,有SR-A表达,主要位于细胞膜,蛋白质印迹技术发现ox-LDL能促进平滑肌细胞SR-A表达。
4.流式细胞术检测提示,FIZZ1 3×10~(-6)mmol/L组与对照组SR-A表达阳性率比较,统计学上有极显著性差异(P<0.01);FIZZ1 9×10~(-6)mmol/L组与FIZZ1 3×10~(-6)mmol/L组SR-A表达阳性率比较,有显著性差异(P<0.05), FIZZ1 2.7×10~(-5)mmol/L组与9×10~(-6)mmol/L组SR-A表达阳性率比较,有极显著性差异(P<0.01),说明FIZZ1能明显促进ox-LDL刺激的平滑肌细胞SR-A表达。
5.ox-LDL明显刺激巨噬细胞CD36表达,FIZZ1不影响体外培养的巨噬细胞清道夫受体CD36的表达,说明FIZZ1不能通过影响巨噬细胞CD36表达来影响巨噬细胞ox-LDL的摄取,影响动脉粥样硬化。
6.ApoE基因敲除鼠高脂饲养21周后,主动脉根部明显形成动脉粥样硬化,血脂代谢明显紊乱,免疫组化可见FIZZ1在粥样硬化斑块内明显表达,辛伐他汀能降低动脉粥样硬化斑块内FIZZ1mRNA及其蛋白表达(与对照组比较,差别具有统计学意义,P<0.05)。
结论
1.FIZZ1在ApoE基因敲除鼠粥样斑块内明显表达,同龄野生型C57BL/6J鼠血管壁内,FIZZ1不表达,FIZZ1可能为一种新的影响动脉粥样硬化进展的促炎因子。
2.Th2型细胞因子可以刺激巨噬细胞FIZZ1表达,但不能刺激平滑肌细胞FIZZ1表达,Th2型细胞因子刺激巨噬细胞可能为斑块内FIZZ1表达机理之一。
3.FIZZ1明显刺激体外培养的主动脉平滑肌细胞增殖。
4.FIZZ1不影响体外培养的巨噬细胞清道夫受体CD36的表达,FIZZ1能促进ox-LDL诱导的体外培养的平滑肌细胞SR-A表达,从而可能加速平滑肌细胞吞噬脂质,促进动脉粥样硬化进展。
5.辛伐他汀能明显减少动脉粥样硬化斑块内FIZZ1表达,减轻动脉粥样硬化,此可能为调脂药物抗动脉粥样硬化的非调脂作用之一。
Background and Objectives
The study of pathogenesis of atherosclerosis (AS) has lasted more than one century. There are four hypotheses: lipid infiltration hypothesis, platelet aggregation (PA) and thrombosis hypothesis, vascular smooth muscle cell (VSMCs) clone hypothesis and response-to-injury hypothesis. In recent years, AS has been identified to resemble some fundamental pathological manifestations of inflammation including alteration, exudation and proliferation. In the development of AS, cell-cell interaction is similar to that in chronic inflammation diseases such as rheumatoid arthritis, chronic pancreatitis, hepaticcirhosis, etc. With the identifying of inflammatory cells and mediators, AS is no longer considered as a simple disease of fatty substance accumulation in the artery wall, but as a progressive inflammatory reaction, which is consistent with the general rule of inflammation. Based on his response-to-injury hypothesis, professor Ross proposed that AS is an inflammation disease. Presently, many inflammatory mediators in AS have been discovered such as PDGF-β,bFGF, TGF-βand VEGF.
FIZZ1 (Found in Inflammatory Zone 1) was discovered by EST in 2000 and identified to be a new hypoxia derivation mitgenic factor associated with inflammation. It is a secreting protein, with the molecular weight of 9.4KD, which has the function of enhancing the proliferation of pulmonary artery VSMCs, contracting blood vessel, promoting the neogenesis of blood vessel, and stimulating myofibroblast differentiation. FIZZ1 can be detected in the stromal blood vessel of adipose tissue and alternatively activated macrophages, as well as anoxic pulmonary vessel wall. Because there are Th2 cytokines and generous alternatively activated macrophages in atherosclerotic plaque, and atherosclerotic vessel wall is usually hypoxic, we presume that FIZZ1 may exist in atherosclerotic plaque. In this study, we detected the expression of FIZZ1 in atherosclerotic plague by immunohistochemistry method, explored the effect of FIZZ1 on the proliferation of VSMCs and the expression of VSMCs scavenger receptor A (SR-A), and investigated the effect of Simvastatin on the expression of FIZZ1 in atherosclerotic plaque.
Methods
The first part: sixteen C57BL/6J ApoE-/- mice were fed with high fat diet while 12 C57BL/6J mice were fed with normal diet. Twenty-four week later, all the mice were executed for the collection of aortas which were dissected from aortic root to abdominal aorta. Then the aortic sections were imbedded with paraffin for HE dying and FIZZ1 immunohistochemistry. At the same time, the expression of FIZZ1 mRNA in atherosclerotic plaque was detected by RT-PCR. In vitro, after Th2 cytokine was used to stimulate cultural VSMCs and macrophage, the expression of FIZZ1 mRNA and protein were detected by RT-PCR and laser confocal microscopy, respectively. The second part: The cultural VSMCs were stimulated with FIZZ1 at different final concentrations of 3×10~(-6)mmol/L, 9×10~(-6)mmol/L and 2.7×10~(-5)mmol/L respectively. Then the effect of FIZZ1 on the proliferation of VSMCs was detected by ~3H-TdR incorporation and MTT. After the cultural VSMCs were stimulated with ox-LDL and FIZZ1 at different final concentrations of 3×10~(-6)mmol/L, 9×10~(-6)mmol/L, 2.7×10~(-5)mmol/L, respectively. Laser confocal microscopy was applied to ascertain and locate the expression of SR-A. Western-blot and flow cytometry were used to detect the effect of FIZZ1 on the expression of SR-A in VSMCs, and meanwhile, flow cytometry was used to detect the effect of FIZZ1 on the expression of CD36 in macrophages.
The third part: The animal models of AS and hyperlipoidemia were established, and then interfered with Simvastatin. 21 weeks later, the effect of Simvastatin on the expression of FIZZ1 was evaluated by RT-PCR and immunohistochemistry. The morphology of atherosclerotic plaque was observed.
Results
1. After 24 weeks, AS emerged obviously in the aortic root in ApoE-/- mice fed with high fat diet, and the area of plaque was fairly large. The expression of FIZZ1 was detected in atherosclerotic plaque by immunohistochemistry and RT-PCR. In the normal artery of C57BL/6J wild type mice, FIZZ1 was negative. Th2-type cytokine can induce the expression of FIZZ1 in macrophages, but not in VSMCs.
2. The proliferation of VSMCs was detected by MTT. Compared to the control group, the A value of FIZZ1 3×10~(-6) mmol/L group increased obviously (P<0.05). Compared to FIZZ1 3×10~(-6) mmol/L group, the A value of FIZZ1 9×10~(-6) mmol/L group increased obviously (P<0.05). Compared to FIZZ1 9×10~(-6) mmol/L group, the A value of FIZZ1 2.7×10~(-5) mmol/L group increased obviously (P<0.05). These results indicated FIZZ1 enhance aorta VSMCs proliferation, which was also observed by 3H-TdR incorporation.
3. SR-A positive expression was found in VSMCs treated with ox-LDL after 24 hours, which located mainly in cell membrane by laser confocal microscopy. SR-A protein was also detected by Western - blot.
4. There were significant differences in SR-A positive rates between FIZZ1 3×10~(-6) mmol/L group and the control group by flow cytometry (P<0.01). The same results were found between FIZZ1 9×10~(-6) mmol/L group and FIZZ1 3×10~(-6) mmol/L group, between FIZZ1 2.7×10~(-5) mmol/L group and FIZZ1 9×10~(-6) mmol/L group, too. These results indicate FIZZ1 enhance the expression of SR-A induced by ox-LDL in VSMCs.
5. FIZZ1 had no effect on the expression of scavenger receptor CD36 in cultured macrophages, which reveals that it couldn’t interfere with the ox-LDL uptake of macrophages and atherosclerosis.
6. After 21 weeks, AS emerged obviously in the aortic root in ApoE-/- mice fed with high fat diet, and lipid metabolism in the mice disordered. FIZZ1 in atherosclerotic plaque was positive by immunohistochemistry. Simvastatin could decrease the expression of FIZZ1 mRNA and protein in atherosclerotic plaque (P<0.05).
Conclusions
1. FIZZ1 can express in the atherosclerotic plaque in C57BL/6J ApoE-/- mice, but not in the normal artery of C57BL/6J wild type mice.
2. Th2-type cytokine can enhance the expression of FIZZ1 in mcrophages, but not in VSMCs. Th2-type cytokine is one of the probable factors which induce the expression of FIZZ1 in atherosclerotic plaque.
3. FIZZ1 can stimulate the proliferation of VSMCs obviously.
4. FIZZ1 had no effect on the expression of scavenger receptor CD36 in cultured macrophages. FIZZ1 can promote the development of AS by the up-regulation of the expression of SR-A and the phagocytose of fatty substance in VSMCs.
5. Simvastatin can decrease the area of plaque and the expression of FIZZ1 in atherosclerotic plaque obviously, which may be a mechanism of anti-AS drug.
动脉粥样硬化(atherosclerosis,AS)发病机制的研究已经经历了一个多世纪,主要围绕4种学说:脂肪浸润学说、血小板聚集和血栓形成学说、平滑肌细胞克隆学说和损伤反应学说,但至今详细发病机理仍未完全阐明。近年来不少研究发现,动脉粥样硬化的病理表现具有炎症病理的基本表现形式:变质、渗出和增生,其形成过程中也会出现类似类风湿性关节炎、慢性胰腺炎和肝硬化等慢性炎症性疾病的细胞间相互作用,随着炎症细胞和炎症介质的不断检出,动脉粥样硬化不再被认为是单纯的动脉壁脂质堆积的疾病,而是进展性炎症反应,符合炎症表现的普遍规律。目前,在动脉粥样硬化发现的促炎因子较多,如血小板源性生长因子β(PDGF-β)、血小板衍生因子(PDEF)、单核细胞趋化蛋白1、白细胞介素3、环氧合酶-2、基质金属蛋白酶、去组合蛋白、脂肪酸结合蛋白等,由于目前临床针对上述介质的抗动脉粥样硬化药物起效缓慢且疗效有待提高,因此是否还有其它炎症因子参与动脉粥样硬化进展有待进一步研究。FIZZ1(Found in Inflammatory Zone 1)是2000年新发现的一个与炎症相关的缺氧诱导有丝分裂因子,是运用表达序列标记数据库扫描的方法发现的一种分泌型蛋白,分子量9.4KD,具有刺激肺动脉平滑肌细胞增殖、收缩血管、促进血管新生、刺激肌纤维母细胞分化等功能,在脂肪组织的间质血管以及选择性激活的巨噬细胞中均有表达,缺氧的肺血管壁也有表达,在实验性肺纤维化、哮喘、过敏性肺炎、寄生虫感染等疾病中具有重要意义,其在动脉粥样硬化中是否表达则为未知,由于动脉粥样硬化斑块内存在Th2型细胞因子以及大量激活的巨噬细胞,动脉粥样硬化的血管壁也存在缺氧,因此,我们推测在动脉粥样硬化斑块内可能有FIZZ1表达。本实验用免疫组织化学方法检测动脉粥样硬化斑块内FIZZ1表达,RT-PCR检测FIZZ1mRNA表达,并探讨FIZZ1对体外培养的平滑肌细胞增殖,平滑肌细胞清道夫受体SR-A,巨噬细胞CD36表达影响,同时探讨降脂治疗对动脉粥样硬化斑块FIZZ1表达的影响。
研究方法
本研究分三部分,第一部分:选取C57BL/6J ApoE基因敲除鼠及C57BL/6J野生型小鼠,分别喂食高脂饲料及普通饲料,24周后处死小鼠,石蜡包埋血管后作连续切片,行HE染色及FIZZ1免疫组化染色,检测斑块FIZZ1表达情况, RT-PCR检测动脉粥样硬化斑块内FIZZ1mRNA表达,然后,模拟粥样斑块内细胞因子环境,用Th2型细胞因子刺激培养的平滑肌细胞以及巨噬细胞,RT-PCR以及激光共聚焦显微镜观察刺激后细胞FIZZ1mRNA及其蛋白表达情况,初步鉴定粥样斑块内分泌FIZZ1的可能的细胞;第二部分用终浓度分别为3×10~(-6)mmol/L,9×10~(-6)mmol/L,2.7×10~(-5)mmol/L的FIZZ1刺激培养的平滑肌细胞,3H掺入法以及MTT法测定FIZZ1对平滑肌细胞增殖的影响;用ox-LDL以及终浓度分别为3×10~(-6)mmol/L , 9×10~(-6)mmol/L , 2.7×10~(-5)mmol/L的FIZZ1刺激培养的平滑肌细胞,蛋白质印迹技术确认SR-A表达后,激光共聚焦显微镜对SR-A表达进行定位,用流式细胞术检测FIZZ1对平滑肌细胞SR-A及其巨噬细胞CD36表达的影响,评价FIZZ1能否影响动脉粥样硬化吞噬脂质的关键受体。第三部分:制作动脉粥样硬化以及高脂血症动物模型,然后用辛伐他汀干预实验动物,21周后,用免疫组化方法检测粥样斑块FIZZ1蛋白表达情况,RT-PCR方法检测FIZZ1mRNA表达情况,同时检测动脉粥样硬化斑块形态及其血脂水平,探讨调脂治疗对FIZZ1表达的影响。
结果
1.ApoE基因敲除鼠高脂饲养24周后,主动脉根部明显形成动脉粥样硬化,斑块体积大,免疫组化可见FIZZ1在动脉粥样硬化斑块内明显表达,RT-PCR可见FIZZ1mRNA表达,同龄野生型C57BL/6J鼠正常血管壁内,未见FIZZ1表达,Th2型细胞因子能刺激培养的巨噬细胞表达FIZZ1,但不能刺激体外培养的平滑肌细胞表达FIZZ1。
2.MTT检测平滑肌细胞增殖提示,FIZZ1 3×10~(-6)mmol/L组与对照组吸光度值比较,明显升高,P<0.05,差异有显著性;FIZZ1 9×10~(-6)mmol/L组与FIZZ1 3×10~(-6)mmol/L组比较,吸光度值明显升高,差异有显著性,P<0.05, FIZZ1 2.7×10~(-5)mmol/L组与9×10~(-6)mmol/L组比较,吸光度值明显升高,差异有显著性,说明FIZZ1能刺激平滑肌细胞增殖。3H-TdR掺入法检测也提示FIZZ1刺激平滑肌细胞增殖。
3.激光共聚焦显微镜可见在ox-LDL刺激24小时的平滑肌细胞,有SR-A表达,主要位于细胞膜,蛋白质印迹技术发现ox-LDL能促进平滑肌细胞SR-A表达。
4.流式细胞术检测提示,FIZZ1 3×10~(-6)mmol/L组与对照组SR-A表达阳性率比较,统计学上有极显著性差异(P<0.01);FIZZ1 9×10~(-6)mmol/L组与FIZZ1 3×10~(-6)mmol/L组SR-A表达阳性率比较,有显著性差异(P<0.05), FIZZ1 2.7×10~(-5)mmol/L组与9×10~(-6)mmol/L组SR-A表达阳性率比较,有极显著性差异(P<0.01),说明FIZZ1能明显促进ox-LDL刺激的平滑肌细胞SR-A表达。
5.ox-LDL明显刺激巨噬细胞CD36表达,FIZZ1不影响体外培养的巨噬细胞清道夫受体CD36的表达,说明FIZZ1不能通过影响巨噬细胞CD36表达来影响巨噬细胞ox-LDL的摄取,影响动脉粥样硬化。
6.ApoE基因敲除鼠高脂饲养21周后,主动脉根部明显形成动脉粥样硬化,血脂代谢明显紊乱,免疫组化可见FIZZ1在粥样硬化斑块内明显表达,辛伐他汀能降低动脉粥样硬化斑块内FIZZ1mRNA及其蛋白表达(与对照组比较,差别具有统计学意义,P<0.05)。
结论
1.FIZZ1在ApoE基因敲除鼠粥样斑块内明显表达,同龄野生型C57BL/6J鼠血管壁内,FIZZ1不表达,FIZZ1可能为一种新的影响动脉粥样硬化进展的促炎因子。
2.Th2型细胞因子可以刺激巨噬细胞FIZZ1表达,但不能刺激平滑肌细胞FIZZ1表达,Th2型细胞因子刺激巨噬细胞可能为斑块内FIZZ1表达机理之一。
3.FIZZ1明显刺激体外培养的主动脉平滑肌细胞增殖。
4.FIZZ1不影响体外培养的巨噬细胞清道夫受体CD36的表达,FIZZ1能促进ox-LDL诱导的体外培养的平滑肌细胞SR-A表达,从而可能加速平滑肌细胞吞噬脂质,促进动脉粥样硬化进展。
5.辛伐他汀能明显减少动脉粥样硬化斑块内FIZZ1表达,减轻动脉粥样硬化,此可能为调脂药物抗动脉粥样硬化的非调脂作用之一。
Background and Objectives
The study of pathogenesis of atherosclerosis (AS) has lasted more than one century. There are four hypotheses: lipid infiltration hypothesis, platelet aggregation (PA) and thrombosis hypothesis, vascular smooth muscle cell (VSMCs) clone hypothesis and response-to-injury hypothesis. In recent years, AS has been identified to resemble some fundamental pathological manifestations of inflammation including alteration, exudation and proliferation. In the development of AS, cell-cell interaction is similar to that in chronic inflammation diseases such as rheumatoid arthritis, chronic pancreatitis, hepaticcirhosis, etc. With the identifying of inflammatory cells and mediators, AS is no longer considered as a simple disease of fatty substance accumulation in the artery wall, but as a progressive inflammatory reaction, which is consistent with the general rule of inflammation. Based on his response-to-injury hypothesis, professor Ross proposed that AS is an inflammation disease. Presently, many inflammatory mediators in AS have been discovered such as PDGF-β,bFGF, TGF-βand VEGF.
FIZZ1 (Found in Inflammatory Zone 1) was discovered by EST in 2000 and identified to be a new hypoxia derivation mitgenic factor associated with inflammation. It is a secreting protein, with the molecular weight of 9.4KD, which has the function of enhancing the proliferation of pulmonary artery VSMCs, contracting blood vessel, promoting the neogenesis of blood vessel, and stimulating myofibroblast differentiation. FIZZ1 can be detected in the stromal blood vessel of adipose tissue and alternatively activated macrophages, as well as anoxic pulmonary vessel wall. Because there are Th2 cytokines and generous alternatively activated macrophages in atherosclerotic plaque, and atherosclerotic vessel wall is usually hypoxic, we presume that FIZZ1 may exist in atherosclerotic plaque. In this study, we detected the expression of FIZZ1 in atherosclerotic plague by immunohistochemistry method, explored the effect of FIZZ1 on the proliferation of VSMCs and the expression of VSMCs scavenger receptor A (SR-A), and investigated the effect of Simvastatin on the expression of FIZZ1 in atherosclerotic plaque.
Methods
The first part: sixteen C57BL/6J ApoE-/- mice were fed with high fat diet while 12 C57BL/6J mice were fed with normal diet. Twenty-four week later, all the mice were executed for the collection of aortas which were dissected from aortic root to abdominal aorta. Then the aortic sections were imbedded with paraffin for HE dying and FIZZ1 immunohistochemistry. At the same time, the expression of FIZZ1 mRNA in atherosclerotic plaque was detected by RT-PCR. In vitro, after Th2 cytokine was used to stimulate cultural VSMCs and macrophage, the expression of FIZZ1 mRNA and protein were detected by RT-PCR and laser confocal microscopy, respectively. The second part: The cultural VSMCs were stimulated with FIZZ1 at different final concentrations of 3×10~(-6)mmol/L, 9×10~(-6)mmol/L and 2.7×10~(-5)mmol/L respectively. Then the effect of FIZZ1 on the proliferation of VSMCs was detected by ~3H-TdR incorporation and MTT. After the cultural VSMCs were stimulated with ox-LDL and FIZZ1 at different final concentrations of 3×10~(-6)mmol/L, 9×10~(-6)mmol/L, 2.7×10~(-5)mmol/L, respectively. Laser confocal microscopy was applied to ascertain and locate the expression of SR-A. Western-blot and flow cytometry were used to detect the effect of FIZZ1 on the expression of SR-A in VSMCs, and meanwhile, flow cytometry was used to detect the effect of FIZZ1 on the expression of CD36 in macrophages.
The third part: The animal models of AS and hyperlipoidemia were established, and then interfered with Simvastatin. 21 weeks later, the effect of Simvastatin on the expression of FIZZ1 was evaluated by RT-PCR and immunohistochemistry. The morphology of atherosclerotic plaque was observed.
Results
1. After 24 weeks, AS emerged obviously in the aortic root in ApoE-/- mice fed with high fat diet, and the area of plaque was fairly large. The expression of FIZZ1 was detected in atherosclerotic plaque by immunohistochemistry and RT-PCR. In the normal artery of C57BL/6J wild type mice, FIZZ1 was negative. Th2-type cytokine can induce the expression of FIZZ1 in macrophages, but not in VSMCs.
2. The proliferation of VSMCs was detected by MTT. Compared to the control group, the A value of FIZZ1 3×10~(-6) mmol/L group increased obviously (P<0.05). Compared to FIZZ1 3×10~(-6) mmol/L group, the A value of FIZZ1 9×10~(-6) mmol/L group increased obviously (P<0.05). Compared to FIZZ1 9×10~(-6) mmol/L group, the A value of FIZZ1 2.7×10~(-5) mmol/L group increased obviously (P<0.05). These results indicated FIZZ1 enhance aorta VSMCs proliferation, which was also observed by 3H-TdR incorporation.
3. SR-A positive expression was found in VSMCs treated with ox-LDL after 24 hours, which located mainly in cell membrane by laser confocal microscopy. SR-A protein was also detected by Western - blot.
4. There were significant differences in SR-A positive rates between FIZZ1 3×10~(-6) mmol/L group and the control group by flow cytometry (P<0.01). The same results were found between FIZZ1 9×10~(-6) mmol/L group and FIZZ1 3×10~(-6) mmol/L group, between FIZZ1 2.7×10~(-5) mmol/L group and FIZZ1 9×10~(-6) mmol/L group, too. These results indicate FIZZ1 enhance the expression of SR-A induced by ox-LDL in VSMCs.
5. FIZZ1 had no effect on the expression of scavenger receptor CD36 in cultured macrophages, which reveals that it couldn’t interfere with the ox-LDL uptake of macrophages and atherosclerosis.
6. After 21 weeks, AS emerged obviously in the aortic root in ApoE-/- mice fed with high fat diet, and lipid metabolism in the mice disordered. FIZZ1 in atherosclerotic plaque was positive by immunohistochemistry. Simvastatin could decrease the expression of FIZZ1 mRNA and protein in atherosclerotic plaque (P<0.05).
Conclusions
1. FIZZ1 can express in the atherosclerotic plaque in C57BL/6J ApoE-/- mice, but not in the normal artery of C57BL/6J wild type mice.
2. Th2-type cytokine can enhance the expression of FIZZ1 in mcrophages, but not in VSMCs. Th2-type cytokine is one of the probable factors which induce the expression of FIZZ1 in atherosclerotic plaque.
3. FIZZ1 can stimulate the proliferation of VSMCs obviously.
4. FIZZ1 had no effect on the expression of scavenger receptor CD36 in cultured macrophages. FIZZ1 can promote the development of AS by the up-regulation of the expression of SR-A and the phagocytose of fatty substance in VSMCs.
5. Simvastatin can decrease the area of plaque and the expression of FIZZ1 in atherosclerotic plaque obviously, which may be a mechanism of anti-AS drug.
引文
1. Stary HC,ChandlerAB,Glagov S,eta1.A definition of initial,fatty streak,and inter- mediate lesions of athemsclerosis: a report from the Committee on Vascular Lesions of the Counsil on Arteriosclerosis,American Heart Association.Circulation 1994,89: 2462-78.
2. Espinola Klein C, Rupprecht HJ ,Blankenberg S ,et a1.Im-pact of infectious burden on extent and long-term prognosis ofatherosclerosis.Circulation,2002 ,105:15221.
3. Lowenhoff T,Gluszko P. Atherosclerosis and rheumatoid arthritis Przegl Lek. 2005; 62(12):1506-9.
4. Peters W,Charo IF.Involvement of chemokine receptor 2 and its ligand,monocyte chemoattractant protein - 1,in the development of atherosclerosis:lessons from knockout mice.Curr Opin Lipidol,2001,12: 175-180.
5. 程翔,廖玉华,炎症与动脉粥样硬化,中华心血管病杂志,2004,32(5),475-477。
6. Holcomb IN, Kabakoff RC, Chan B,et a1.FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 2000, 19(15):4046-4052.
7. Steppan CM, Brown EJ, Wright CM ,et a1.A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci U S A. 2001 ,98(2):502-506.
8. Beltowski J. Adiponectin and resistin--new hormones of white adipose tissue. Med Sci Monit. 2003,9(2):55-61.
9. Teng X, Li D, Champion HC,et a1.FIZZ1/RELMalpha, a novel hypoxia-induced mito -genic factor in lung with vasoconstrictive and angiogenic properties. Circ Res. 2003, 92(10):1065-1067.
10. Liu T, Dhanasekaran SM, Jin H, et al. FIZZ1 stimulation of myofibroblast differentiation. Am J Pathol. 2004 ,164(4):1315-1326.
11. Liu T, Jin H, Ullenbruch M, et al. Regulation of found in inflammatory zone 1 expression in bleomycin-induced lung fibrosis: role of IL-4/IL-13 and mediation via STAT-6. J Immunol. 2004,173(5):3425-3431.
12. Tong Q, Zheng L, Lin L,et a1.hypoxia-induced mitogenic factor promotes vascularadhesion molecule-1 expression via the PI-3K/Akt-NF-kappaB signaling pathway.Am J Respir Cell Mol Biol. 2006;35(4):444-56.
13. Reece JJ, Siracusa MC, Scott AL. et a1.Innate immune responses to lung-stage helminth infection induce alternatively activated alveolar macrophages. Infect Immun. 2006 ;74(9):4970-81.
14. Aria Febbraio, David P. Hajjar. CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism 20J.Clin Invest, 2001, 108( 6), 785-791.
15. 张骅,楼定安,单子茵,毛峥嵘,魏克荣. 巨噬细胞对肌源性泡沫细胞生成的影响。中国动脉硬化杂志 ,1996,21(04),52-53.
16. T. Bjornheden, M. Levin, M. Evaldsson, et al. Evidence of Hypoxic Areas Within the Arterial Wall In Vivo. Arterioscler Thromb Vasc Biol. 1999;19(2):870-876.
17. 杨永宗主编,动脉粥样硬化性心血管病基础与临床,北京:科学出版社,2004,150-151.
18. J.萨姆布鲁克,EF 弗里奇,T 曼尼阿蒂斯.分子克隆实验指南[M].北京:科学出版社,2002,870-898.
19. 任立群,张秀云,孙波,等.大鼠胸主动脉平滑肌细胞的组织贴块法培育及鉴定.吉林大学学报(医学版).2002;28(2):135-138.
20. 薛庆善主编,体外培养的原理与技术,北京:科学出版社,2001,453-456.
21. Hansson GK.Immune mechanisms in atherosclerosis.Atheriosclerosis .Thromb Vas Biol,2001,21:1876-1890.
22. Kunjathoor VV ,Febbraio M,Podrez EA,etal. Scavenger receptors class A-L/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages.J Biol Chem,2002,277(51) :49982-8.
23. Koki A,KhanNK, Olson L,et a1.Cyelooxygenase-2 in human pathological disease.Adv Exp Med Biol,2002,507:177-184.
24. Dixon DA, Tolley ND, Bemis-Standoli K, et a1. Expression of COX-2 in platelet -monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling. J Clin Invest. 2006 ;116(10):2727-38.
25. Johnson JL. atrix metalloproteinases: influence on smooth muscle cells and atherosclerotic plaque stability. Expert Rev Cardiovasc Ther. 2007 ;5(2):265-82.
26. Boord JB, Maeda K, Makowski L, Babaev VR, Fazio S, Linton MF, Hotamisligil GS. Combined adipocyte-macrophage fatty acid-binding protein eficiency improves metabolism, atherosclerosis, and survival in apolipoprotein E-deficient mice. Circulation. 2004 ;110(11):1492-8.
27. Gerstmayer B, Kusters D, Gebel S, Muller T, et al.Identification of RELMgamma, a novel resistin-like molecule with a distinct expression pattern. Genomics. 2003, 81(6):588-595.
28. He W, Wang ML, Jiang HQ .Bacterial colonization leads to the colonic secretion of RELMbeta/FIZZ2, a novel goblet cell-specific protein. Gastroenterology. 2003; 125 (5):1388-1397.
29. Artis D, Wang ML, Keilbaugh SA, et al. RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci U S A. 2004 ;101(37):13596-13600.
30. Utzschneider KM, Carr DB, Tong J, et al. Resistin is not associated with insulin sensitivity or the metabolic syndrome in humans. Diabetologia. 2005; 48(11): 2330-3.
31. Stutz AM, Pickart LA, Trifilieff A ,et al.The Th2 cell cytokines IL-4 and IL-13 regulate found in inflammatory zone1/resistin-like molecule alpha gene expression by a STAT6 and CCAAT/enhancer-binding protein-dependent mechanism. J Immunol. 2003, 170(4):1789-1796.
32. 冯宗忱.动脉粥样硬化-血管壁的慢性炎症.中华心血管病杂志,2005,33 (5),393-394.
33. xinghua Zhou, Gabrielle Paulsson, Sten Stemme,et a1. Hypercholesterolemia Is Asso -ciated with a T Helper (Th) 1/Th2 Switch of the Autoimmune Response in Atherosclerotic apo E-knockout Mice. J. Clin. Invest. 1998,101:1717-1725.
34. Nair MG, Gallagher IJ, Taylor MD, et al. Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun. 2005,73(1):385-394.
35. Donnelly S, O'Neill SM, Sekiya M, et al.Thioredoxin peroxidase secreted by Fasciola hepatica induces the alternative activation of macrophages. Infect Immun. 2005, 73(1): 166-173.
36. Raes G, Brys L, Dahal BK, et al. Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation.J Leukoc Biol. 2005,77(3):321-327.
37. Tong Q, Zheng L, Lin L,et a1. ypoxia-induced mitogenic factor promotes vascular adhesion molecule-1 expression via the PI-3K/Akt-NF-kappaB signaling pathway. Am J Respir Cell Mol Biol. 2006 ;35(4):444-56.
38. 薛庆善主编 体外培养的原理与技术,北京:科学出版社,2001,342-443.
39. 胡厚源,陈运贞. 单核细胞趋化蛋白-1 对其表面淋巴细胞功能相关抗原-1、清道夫受体和载脂蛋白 E 表达的影响及雌二醇的干预作用. 中国动脉硬化杂志 ,2000,(04),61-65.
40. 刘瑞,马爱群,郝春瑗等,单核细胞与内皮细胞的相互作用对单核细胞 CD36 表达的影响。中国病理生理杂志,2004,20,30351-353.
41. 杨永宗主编,动脉粥样硬化性心血管病基础与临床,北京:科学出版社,2004,52-53.
42. Li D, Fernandez LG, Dodd-o J, et al. Upregulation of hypoxia-induced mitogenic factor in compensatory lung growth after pneumonectomy. Am J Respir Cell Mol Biol. 20 05,32:185-91.
43. Nicholson AC, Hajjar DP. CD36, oxidized LDL and PPAR gamma: pathological interactions in macrophages and atherosclerosis. Vascul Pharmacol.2004;41 (5) : 39-146
44. Febbraio M, Podrez EA, Smith JD, et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J. Clin. Invest. 2000,105(8): 1049-1056.
45. Maria Febbraio, David P. Hajjar. et a1.CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism 20J Clin Invest, 2001, 108( 6), 785-791.
46. Lam MC, Tan KC, Lam KS. et a1.Glycoxidized low-density lipoprotein regulates the expression of scavenger receptors in THP-1 macrophages. Atherosclerosis. 2004 Dec;177(2):313-20.
47. 孙永慧,杨永宗,清道夫受体 A 与动脉粥样硬化,心血管病学进展,2005,26(6),585-587
48. Kamada N, Kodama T, Suzuki H. et a1.Macrophage scavenger receptor (SR-A I/II) deficiency reduced diet-induced atherosclerosis in C57BL/6J mice. J Atheroscler Thromb. 2001;8(1):1-6.
49. Tamura Y, Osuga J, Adachi H,et a1. Scavenger receptor expressed by endothelial cells I (SREC-I) mediates the uptake of acetylated low density lipoproteins bymacrophages stimulated with lipopolysaccharide. J Biol Chem. 2004; 279 (30):30938-44.
50. Horiuchi S, Sakamoto Y, Sakai M. Scavenger receptors for oxidized and glycated proteins. Amino Acids. 2003 ;25(3-4):283-92.
51. Linton MF, Fazio S. Macrophages, inflammation, and atherosclerosis. Int J Obes Relat Metab Disord. 2003 ;27 Suppl 3:S35-40.
52. Shashkin P, Dragulev B, Ley K. et a1.Macrophage differentiation to foam cells. Curr Pharm Des. 2005;11(23):3061-72.
53. Chen M, Cybulsky MI, Moore KJ,et a1.Luscher TF. Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science. 2004 Nov 26;306(5701):1558-61.
54. Peiser L,Gordon S. The function of scavenger receptors expressed by macrophages and their role in the regulation of inflammation. Microbes Infect. 2001;3(2):149-59.
55. Hu YZ, Dong YG, Zhai YF,et a1.Effects of simvastatin on homocysteine-induced endothelial dysfunction and inflammatory response. Zhonghua Yi Xue Za Zhi. 2006 ;86(32):2297-300.
56. Pozo M, de Nicolas R, Egido J,et a1. Simvastatin inhibits the migration and adhesion of monocytic cells and disorganizes the cytoskeleton of activated endothelial cells. Eur J Pharmacol. 2006 ,24;548(1-3):53-63.
57. Landsberger M, Wolff B, Jantzen F, et a1. Cerivastatin reduces cytokine-induced surface expression of ICAM-1 via increased shedding in human endothelial cells. Atherosclerosis. 2007 ;190(1):43-52.
58. 张新超,徐成斌,王胜洵,普伐他汀对 ApoE 缺陷小鼠主动脉粥样硬化及主动脉壁细胞间黏附分子-1 表达的影响。中华老年医学杂志,2001,20(6)418-420。
59. 杨永宗主编,动脉粥样硬化性心血管病基础与临床,北京:科学出版社,2004,150-151.
60. Asahi M, Huang Z, Thomas S, et a1.Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. J Cereb Blood Flow Metab. 2005;25(6):722-9.
61. Eto M, Rathgeb L, Cosentino F,et a1. Statins blunt thrombin-induced down-regulation of endothelial nitric oxide synthase expression in human endothelial cells. J Cardiovasc Pharmacol. 2006;47(5):663-7.
62. Li JJ, Fang CH, Wang C,et a1. Effects of simvastatin on exercise-induced myocardial ischemia and plasma endothelin-1 concentrations in patients with stable angina. ClinChim Acta. 2005;354(1-2):205-8.
63. Ding QF, Chen ZQ, Yin ZW,et a1. Effects of Zhikeping on aortic oxyradical and the expression of ICAM-1 in a rat model of experimental early atherosclerosis . Zhongguo Zhong Yao Za Zhi. 2006 Mar;31(5):407-10.
64. Alber HF, Frick M, Sussenbacher A, Dorler J, Dichtl W, Stocker EM,Pachinger O, Weidinger F. Effect of atorvastatin on peripheral endothelial function and systemic inflammatory markers in patients with stable coronary artery disease.Wien Med Wochenschr. 2007 Feb;157(3-4):73-78.
65. Marketou ME, Zacharis EA, Nikitovic D,et a1. Early effects of simvastatin versus atorvastatin on oxidative stress and proinflammatory cytokines in hyperlipidemic subjects.Angiology. 2006 Mar-Apr;57(2):211-8.
66. Nachtigal P, Pospisilova N, Pospechova K, et a1. MDOC and atorvastatin have pot -ential antiinflammatory effects in vascular endothelium of ApoE-/- mouse model of atherosclerosis. Life Sci. 2006;78(17):1983-9.
67. Yasuda S, Miyazaki S, Kinoshita H,et a1. Enhanced cardiac production of matrix metalloproteinase-2 and -9 and its attenuation associated with pravastatin treatment in patients with acute myocardial infarction. Clin Sci (Lond). 2007 ;112(1):43-9.
68. Schafer A, Fraccarollo D, Vogt C,et a1.Improved endothelial function and reduced platelet activation by chronic HMG-CoA-reductase inhibition with rosuvastatin in rats with streptozotocin-induced diabetes mellitus. Biochem Pharmacol. 2007 1;73 (9): 1367-75.
69. 叶红; 马万里; 张少华;慢性吸烟大鼠肺组织 FIZZ1/REL Mα 表达的变化中国病理生理杂志,2006,22(5),938-942.
70. Nitenberg A. Hypertension, endothelial dysfunction and cardiovascular risk. Arch Mal Coeur Vaiss. 2006;99(10):915-21.
71. Yamaji-Kegan K, Su Q, Angelini DJ,et a1.Hypoxia-induced mitogenic factor has proangiogenic and proinflammatory effects in the lung via VEGF and VEGF receptor-2. Am J Physiol Lung Cell Mol Physiol. 2006 ;291(6):L1159-68.
72. Lucerna M, Zernecke A, de Nooijer R, et al. endothelial growth factor-A induces plaque expansion in ApoE knock-out mice by promoting de novo leukocyte recruitment. Blood. 2007;109(1):122-9.
1. Holcomb IN, Kabakoff RC, Chan B,et al. Baker TW, FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 2000 ,19(15):4046-4052.
2. Steppan CM, Brown EJ, Wright CM ,et al .A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci U S A. 2001 ,98(2):502-506.
3. Teng X, Li D, Champion HC, Johns RA. FIZZ1/RELMalpha, a novel hypoxia-induced mitogenic factor in lung with vasoconstrictive and angiogenic properties. Circ Res. 2003,92(10):1065-1067.
4. Beltowski J. Adiponectin and resistin--new hormones of white adipose tissue. Med Sci Monit. 2003,9(2):55-61.
5. Gerstmayer B, Kusters D, Gebel S, Muller T, et al.Identification of RELMgamma, a novel resistin-like molecule with a distinct expression pattern. Genomics. 2003, 81 (6):588-595.
6. Blagoev B, Kratchmarova I, Nielsen MM, et al. Inhibition of adipocyte differentiation by resistin-like molecule alpha. Biochemical characterization of its oligomeric nature. J Biol Chem. 2002 ,277(44):42011-42016.
7. Goncharova EA, Ammit AJ, Irani C, et al.PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2002,283(2):354-363.
8. 马万里,叶红,陶晓南 实验性肺纤维化大鼠发病过程中肺组织 FIZZ1 的动态变化 生理学报,2005,57(4):493-497.
9. Misson P, van den Brule S, Barbarin V, et al. Markers of macrophage differentiation in experimental silicosis. J Leukoc Biol. 2004,76(5):926-932.
10. Liu T, Dhanasekaran SM, Jin H, et al.FIZZ1 stimulation of myofibroblast differentiation. Am J Pathol. 2004 ,164(4):1315-1326.
11. Liu T, Jin H, Ullenbruch M, et al. Regulation of found in inflammatory zone 1 expression in bleomycin-induced lung fibrosis: role of IL-4/IL-13 and mediation via STAT-6. J Immunol. 2004,173(5):3425-3431.
12. Stutz AM, Pickart LA, Trifilieff A ,et al.The Th2 cell cytokines IL-4 and IL-13 regulate found in inflammatory zone1/resistin-like molecule alpha gene expression by a STAT6 and CCAAT/enhancer-binding protein-dependent mechanism. J Immunol. 2003,170(4):1789-1796.
13. Li D, Fernandez LG, Dodd-o J, et al. Upregulation of hypoxia-induced mitogenic factor in compensatory lung growth after pneumonectomy. Am J Respir Cell Mol Biol. 2005,32(3):185-191.
14. Wagner KF, Hellberg AK, Balenger S, et al. Hypoxia-induced mitogenic factor has antiapoptotic action and is upregulated in the developing lung: coexpression with hypoxia-inducible factor-2alpha. Am J Respir Cell Mol Biol. 2004,31(3):276-282.
15. Nair MG, Cochrane DW, Allen JE. et al. Macrophages in chronic type 2 inflammation have a novel phenotype characterized by the abundant expression of Ym1 and Fizz1 that can be partly replicated in vitro. Immunol Lett. 2003 ,85(2):173-180.
16. Raes G, Brys L, Dahal BK, et al. Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation.J Leukoc Biol. 2005,77(3):321-327.
17. Noel W, Hassanzadeh G, Raes G, et al.Infection stage-dependent modulation of macrophage activation in Trypanosoma congolense-resistant and -susceptible mice. Infect Immun. 2002,70(11):6180-6187.
18. Nair MG, Gallagher IJ, Taylor MD, et al. Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun. 2005,73(1):385-394.
19. Yamaji-Kegan K, Su Q, Angelini DJ,et a1. Hypoxia-induced mitogenic factor has proangiogenic and proinflammatory effects in the lung via VEGF and VEGF receptor-2. Am J Physiol Lung Cell Mol Physiol. 2006 ;291(6):L1159-68.
20. Tong Q, Zheng L, Lin L,et a1.hypoxia-induced mitogenic factor promotes vascular adhesion molecule-1 expression via the PI-3K/Akt-NF-kappaB signaling pathway.Am J Respir Cell Mol Biol. 2006;35(4):444-56.
1. Holcomb IN, Kabakoff RC, Chan B,et al. Baker TW, FIZZ1, a novel cysteine- rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 2000;19(15):4046-4052.
2. Steppan CM, Brown EJ, Wright CM ,et al .A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci U S A. 2001;98(2):502-506.
3. Gerstmayer B, Kusters D, Gebel S, Muller T, et al.Identification of RELMgamma, a novel resistin-like molecule with a distinct expression pattern. Genomics. 2003; 81 (6):588-595.
4. Liu T, Jin H, Ullenbruch M, et al. Regulation of found in inflammatory zone via STAT-6. J Immunol. 2004;173(5):3425-3431.
5. Teng X, Li D, Champion HC, et al. FIZZ1/RELMalpha, a novel hypoxia-induced mitogenic factor in lung with vasoconstrictive and angiogenic properties. Circ Res. 2003;92(10):1065-1067.
6. Misson P, van den Brule S, Barbarin V, et al. Markers of macrophage differentiation in experimental silicosis. J Leukoc Biol. 2004;76(5):926-932.
7. Li D, Fernandez LG, Dodd-o J, et al. Upregulation of hypoxia-induced mitogenic factor in compensatory lung growth after pneumonectomy. Am J Respir Cell Mol Biol. 2005;32(3):185-191.
8. Nair MG, Gallagher IJ, Taylor MD, et al. Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun. 2005;73(1):385-394.
9. Donnelly S, O'Neill SM, Sekiya M, et al.Thioredoxin peroxidase secreted by Fasciola hepatica induces the alternative activation of macrophages. Infect Immun. 2005;73(1):166-173.
10. Rajala MW, Lin Y, Ranalletta M, et al.Cell type-specific expression and coregulation of murine resistin and resistin-like molecule-alpha in adipose tissue. Mol Endocrinol. 2002 ;16(8):1920-1930.
11. He W, Wang ML, Jiang HQ .Bacterial colonization leads to the colonic secretion of RELMbeta/FIZZ2, a novel goblet cell-specific protein. Gastroenterology. 2003 ; 125(5):1388-1397.
12. Artis D, Wang ML, Keilbaugh SA, et al. RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci U S A. 2004 ;101(37):13596-13600.
13. Banerjee RR, Lazar MA. Dimerization of resistin and resistin-like molecules is determined by a single cysteine. J Biol Chem. 2001;276(28):25970-25973.
14. Kim KH, Lee K, Moon YS, et al. A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. J Biol Chem. 2001;276(14):11252-11256.
15. Yang RZ, Huang Q, Xu A, et al. Comparative studies of resistin expression and phylogenomics in human and mouse. Biochem Biophys Res Commun. 2003 ; 310(3):927-935.
16. Morash BA, Willkinson D, Ur E, et al. Resistin expression and regulation in mouse pituitary. FEBS Lett. 2002;526(1-3):26-30.
17. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409(6818):307-312.
18. Nagaev I, Smith U. Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem Biophys Res Commun. 2001;285(2):561-564.
19. Utzschneider KM, Carr DB, Tong J, et al. Resistin is not associated with insulin sensitivity or the metabolic syndrome in humans. Diabetologia. 2005;48 (11): 2330-3.
20. 许莉军,张木勋 Resistin 与胰岛素抵抗 .中国微循环 2004;8(1):286-289。
21. Shojima N, Sakoda H, Ogihara T, et al.Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes. 2002 ;51(6):1737-1744.
22. Schinke T, Haberland M, Jamshidi A. Cloning and functional characterization of resistin-like molecule gamma. Biochem Biophys Res Commun. 2004 ;314 (2): 356-362.
23. Shojima N, Ogihara T, Inukai K.et al. Serum concentrations of resistin-like molecules beta and gamma are elevated in high-fat-fed and obese db/db mice, with increased production in the intestinal tract and bone marrow.Diabetologia. 2005; 48 (5): 984-992.
24. Kushiyama A, Shojima N, Ogihara T, et al. Resistin like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes and induces diabetes.J Biol Chem.2005;280(51):42016-25.
25. 陈江,洪雪,马志兰. 尿内皮素在糖尿病患者肾脏微血管早期损害的诊断价值.中国微循环.2004;8(5):60-63.
26. Reilly MP, Lehrke M, Wolfe ML, et al. Resistin is an inflammatory marker of atherosclerosis in humans. Circulation. 2005;111(7):932-939.
27. Burnett MS, Devaney JM, Adenika RJ, et al. Cross Sectional Associations of Resistin, Coronary Heart Disease and Insulin Resistance. J Clin Endocrinol Metab. 2006;91(1):64-8.
28. 章建梁 秦永文 郑 兴等。 血清抵抗素浓度与血压的相关性研究.解放军医学杂志 2003;28(3):241-245.
29. 毛红仙 汪大望 郑景晨等。血浆抵抗素与 2 型糖尿病的相关性. 中华糖尿病杂志 2005 ;13(4):274-276.
1. Holcomb IN, Kabakoff RC, Chan B,et al. Baker TW, FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 2000 ,19:4046-4052.
2. Steppan CM, Brown EJ, Wright CM ,et al .A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci U S A. 2001 ,98:502-506.
3. Gerstmayer B, Kusters D, Gebel S, Muller T, et al.Identification of RELMgamma, a novel resistin-like molecule with a distinct expression pattern. Genomics. 2003, 81: 588-595.
4. Beltowski J. Adiponectin and resistin--new hormones of white adipose tissue. Med Sci Monit. 2003,9:RA55-61.
5. Blagoev B, Kratchmarova I, Nielsen MM, et al. Inhibition of adipocyte differentiation by resistin-like molecule alpha. Biochemical characterization of its oligomeric nature. J Biol Chem. 2002 ,277:42011-42016.
6. Teng X, Li D, Champion HC, Johns RA. FIZZ1/RELMalpha, a novel hypoxia-induced mitogenic factor in lung with vasoconstrictive and angiogenic properties. Circ Res. 2003,92:1065-1067.
7. Goncharova EA, Ammit AJ, Irani C, et al.PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2002,283:L354-363.
8. Liu T, Jin H, Ullenbruch M, et al. Regulation of found in inflammatory zone 1 expression in bleomycin-induced lung fibrosis: role of IL-4/IL-13 and mediation via STAT-6. J Immunol. 2004 ,173:3425-3431.
9. Stutz AM, Pickart LA, Trifilieff A ,et al.The Th2 cell cytokines IL-4 and IL-13 regulate found in inflammatory zone1/resistin-like molecule alpha gene expression by a STAT6 and CCAAT/enhancer-binding protein-dependent mechanism. J Immunol. 2003, 170: 1789-1796.
10. Nair MG, Cochrane DW, Allen JE. et al. Macrophages in chronic type 2 inflammation have a novel phenotype characterized by the abundant expression of Ym1 and Fizz1 that can be partly replicated in vitro. Immunol Lett. 2003 ,85(2):173-180.
11. Nair MG, Gallagher IJ, Taylor MD, et al. Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun. 2005,73(1):385-394.
12. Donnelly S, O'Neill SM, Sekiya M, et al.Thioredoxin peroxidase secreted by Fasciola hepatica induces the alternative activation of macrophages. Infect Immun. 2005, 73 (1):166-173.
13. Raes G, Brys L, Dahal BK, et al. Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation.J Leukoc Biol. 2005,77(3):321-327.
14. Raes G, De Baetselier P, Noel W, et al, Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages. J Leukoc Biol. 2002 ,71 (4): 597-602.
15. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003 ,3(1):23-35.
16. Rajala MW, Lin Y, Ranalletta M, et al.Cell type-specific expression and coregulation of murine resistin and resistin-like molecule-alpha in adipose tissue. Mol Endocrinol. 2002 ;16(8):1920-30.
17. Misson P, van den Brule S, Barbarin V, et al. Markers of macrophage differentiation in experimental silicosis. J Leukoc Biol. 2004,76:926-932.
18. Shojima N, Sakoda H, Ogihara T, et al. Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes. 2002;51(6):1737-44.
19. Li D, Fernandez LG, Dodd-o J, et al. Upregulation of hypoxia-induced mitogenic factor in compensatory lung growth after pneumonectomy. Am J Respir Cell Mol Biol. 2005,32(3):185-91.
20. Liu T, Dhanasekaran SM, Jin H, et al. FIZZ1 stimulation of myofibroblast different -tiation. Am J Pathol. 2004 ,164:1315-1326.
21. Tong Q, Zheng L, Lin L,et a1.hypoxia-induced mitogenic factor promotes vascular adhesion molecule-1 expression via the PI-3K/Akt-NF-kappaB signaling pathway.Am J Respir Cell Mol Biol. 2006;35(4):444-56.
2. Espinola Klein C, Rupprecht HJ ,Blankenberg S ,et a1.Im-pact of infectious burden on extent and long-term prognosis ofatherosclerosis.Circulation,2002 ,105:15221.
3. Lowenhoff T,Gluszko P. Atherosclerosis and rheumatoid arthritis Przegl Lek. 2005; 62(12):1506-9.
4. Peters W,Charo IF.Involvement of chemokine receptor 2 and its ligand,monocyte chemoattractant protein - 1,in the development of atherosclerosis:lessons from knockout mice.Curr Opin Lipidol,2001,12: 175-180.
5. 程翔,廖玉华,炎症与动脉粥样硬化,中华心血管病杂志,2004,32(5),475-477。
6. Holcomb IN, Kabakoff RC, Chan B,et a1.FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 2000, 19(15):4046-4052.
7. Steppan CM, Brown EJ, Wright CM ,et a1.A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci U S A. 2001 ,98(2):502-506.
8. Beltowski J. Adiponectin and resistin--new hormones of white adipose tissue. Med Sci Monit. 2003,9(2):55-61.
9. Teng X, Li D, Champion HC,et a1.FIZZ1/RELMalpha, a novel hypoxia-induced mito -genic factor in lung with vasoconstrictive and angiogenic properties. Circ Res. 2003, 92(10):1065-1067.
10. Liu T, Dhanasekaran SM, Jin H, et al. FIZZ1 stimulation of myofibroblast differentiation. Am J Pathol. 2004 ,164(4):1315-1326.
11. Liu T, Jin H, Ullenbruch M, et al. Regulation of found in inflammatory zone 1 expression in bleomycin-induced lung fibrosis: role of IL-4/IL-13 and mediation via STAT-6. J Immunol. 2004,173(5):3425-3431.
12. Tong Q, Zheng L, Lin L,et a1.hypoxia-induced mitogenic factor promotes vascularadhesion molecule-1 expression via the PI-3K/Akt-NF-kappaB signaling pathway.Am J Respir Cell Mol Biol. 2006;35(4):444-56.
13. Reece JJ, Siracusa MC, Scott AL. et a1.Innate immune responses to lung-stage helminth infection induce alternatively activated alveolar macrophages. Infect Immun. 2006 ;74(9):4970-81.
14. Aria Febbraio, David P. Hajjar. CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism 20J.Clin Invest, 2001, 108( 6), 785-791.
15. 张骅,楼定安,单子茵,毛峥嵘,魏克荣. 巨噬细胞对肌源性泡沫细胞生成的影响。中国动脉硬化杂志 ,1996,21(04),52-53.
16. T. Bjornheden, M. Levin, M. Evaldsson, et al. Evidence of Hypoxic Areas Within the Arterial Wall In Vivo. Arterioscler Thromb Vasc Biol. 1999;19(2):870-876.
17. 杨永宗主编,动脉粥样硬化性心血管病基础与临床,北京:科学出版社,2004,150-151.
18. J.萨姆布鲁克,EF 弗里奇,T 曼尼阿蒂斯.分子克隆实验指南[M].北京:科学出版社,2002,870-898.
19. 任立群,张秀云,孙波,等.大鼠胸主动脉平滑肌细胞的组织贴块法培育及鉴定.吉林大学学报(医学版).2002;28(2):135-138.
20. 薛庆善主编,体外培养的原理与技术,北京:科学出版社,2001,453-456.
21. Hansson GK.Immune mechanisms in atherosclerosis.Atheriosclerosis .Thromb Vas Biol,2001,21:1876-1890.
22. Kunjathoor VV ,Febbraio M,Podrez EA,etal. Scavenger receptors class A-L/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages.J Biol Chem,2002,277(51) :49982-8.
23. Koki A,KhanNK, Olson L,et a1.Cyelooxygenase-2 in human pathological disease.Adv Exp Med Biol,2002,507:177-184.
24. Dixon DA, Tolley ND, Bemis-Standoli K, et a1. Expression of COX-2 in platelet -monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling. J Clin Invest. 2006 ;116(10):2727-38.
25. Johnson JL. atrix metalloproteinases: influence on smooth muscle cells and atherosclerotic plaque stability. Expert Rev Cardiovasc Ther. 2007 ;5(2):265-82.
26. Boord JB, Maeda K, Makowski L, Babaev VR, Fazio S, Linton MF, Hotamisligil GS. Combined adipocyte-macrophage fatty acid-binding protein eficiency improves metabolism, atherosclerosis, and survival in apolipoprotein E-deficient mice. Circulation. 2004 ;110(11):1492-8.
27. Gerstmayer B, Kusters D, Gebel S, Muller T, et al.Identification of RELMgamma, a novel resistin-like molecule with a distinct expression pattern. Genomics. 2003, 81(6):588-595.
28. He W, Wang ML, Jiang HQ .Bacterial colonization leads to the colonic secretion of RELMbeta/FIZZ2, a novel goblet cell-specific protein. Gastroenterology. 2003; 125 (5):1388-1397.
29. Artis D, Wang ML, Keilbaugh SA, et al. RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci U S A. 2004 ;101(37):13596-13600.
30. Utzschneider KM, Carr DB, Tong J, et al. Resistin is not associated with insulin sensitivity or the metabolic syndrome in humans. Diabetologia. 2005; 48(11): 2330-3.
31. Stutz AM, Pickart LA, Trifilieff A ,et al.The Th2 cell cytokines IL-4 and IL-13 regulate found in inflammatory zone1/resistin-like molecule alpha gene expression by a STAT6 and CCAAT/enhancer-binding protein-dependent mechanism. J Immunol. 2003, 170(4):1789-1796.
32. 冯宗忱.动脉粥样硬化-血管壁的慢性炎症.中华心血管病杂志,2005,33 (5),393-394.
33. xinghua Zhou, Gabrielle Paulsson, Sten Stemme,et a1. Hypercholesterolemia Is Asso -ciated with a T Helper (Th) 1/Th2 Switch of the Autoimmune Response in Atherosclerotic apo E-knockout Mice. J. Clin. Invest. 1998,101:1717-1725.
34. Nair MG, Gallagher IJ, Taylor MD, et al. Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun. 2005,73(1):385-394.
35. Donnelly S, O'Neill SM, Sekiya M, et al.Thioredoxin peroxidase secreted by Fasciola hepatica induces the alternative activation of macrophages. Infect Immun. 2005, 73(1): 166-173.
36. Raes G, Brys L, Dahal BK, et al. Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation.J Leukoc Biol. 2005,77(3):321-327.
37. Tong Q, Zheng L, Lin L,et a1. ypoxia-induced mitogenic factor promotes vascular adhesion molecule-1 expression via the PI-3K/Akt-NF-kappaB signaling pathway. Am J Respir Cell Mol Biol. 2006 ;35(4):444-56.
38. 薛庆善主编 体外培养的原理与技术,北京:科学出版社,2001,342-443.
39. 胡厚源,陈运贞. 单核细胞趋化蛋白-1 对其表面淋巴细胞功能相关抗原-1、清道夫受体和载脂蛋白 E 表达的影响及雌二醇的干预作用. 中国动脉硬化杂志 ,2000,(04),61-65.
40. 刘瑞,马爱群,郝春瑗等,单核细胞与内皮细胞的相互作用对单核细胞 CD36 表达的影响。中国病理生理杂志,2004,20,30351-353.
41. 杨永宗主编,动脉粥样硬化性心血管病基础与临床,北京:科学出版社,2004,52-53.
42. Li D, Fernandez LG, Dodd-o J, et al. Upregulation of hypoxia-induced mitogenic factor in compensatory lung growth after pneumonectomy. Am J Respir Cell Mol Biol. 20 05,32:185-91.
43. Nicholson AC, Hajjar DP. CD36, oxidized LDL and PPAR gamma: pathological interactions in macrophages and atherosclerosis. Vascul Pharmacol.2004;41 (5) : 39-146
44. Febbraio M, Podrez EA, Smith JD, et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J. Clin. Invest. 2000,105(8): 1049-1056.
45. Maria Febbraio, David P. Hajjar. et a1.CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism 20J Clin Invest, 2001, 108( 6), 785-791.
46. Lam MC, Tan KC, Lam KS. et a1.Glycoxidized low-density lipoprotein regulates the expression of scavenger receptors in THP-1 macrophages. Atherosclerosis. 2004 Dec;177(2):313-20.
47. 孙永慧,杨永宗,清道夫受体 A 与动脉粥样硬化,心血管病学进展,2005,26(6),585-587
48. Kamada N, Kodama T, Suzuki H. et a1.Macrophage scavenger receptor (SR-A I/II) deficiency reduced diet-induced atherosclerosis in C57BL/6J mice. J Atheroscler Thromb. 2001;8(1):1-6.
49. Tamura Y, Osuga J, Adachi H,et a1. Scavenger receptor expressed by endothelial cells I (SREC-I) mediates the uptake of acetylated low density lipoproteins bymacrophages stimulated with lipopolysaccharide. J Biol Chem. 2004; 279 (30):30938-44.
50. Horiuchi S, Sakamoto Y, Sakai M. Scavenger receptors for oxidized and glycated proteins. Amino Acids. 2003 ;25(3-4):283-92.
51. Linton MF, Fazio S. Macrophages, inflammation, and atherosclerosis. Int J Obes Relat Metab Disord. 2003 ;27 Suppl 3:S35-40.
52. Shashkin P, Dragulev B, Ley K. et a1.Macrophage differentiation to foam cells. Curr Pharm Des. 2005;11(23):3061-72.
53. Chen M, Cybulsky MI, Moore KJ,et a1.Luscher TF. Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science. 2004 Nov 26;306(5701):1558-61.
54. Peiser L,Gordon S. The function of scavenger receptors expressed by macrophages and their role in the regulation of inflammation. Microbes Infect. 2001;3(2):149-59.
55. Hu YZ, Dong YG, Zhai YF,et a1.Effects of simvastatin on homocysteine-induced endothelial dysfunction and inflammatory response. Zhonghua Yi Xue Za Zhi. 2006 ;86(32):2297-300.
56. Pozo M, de Nicolas R, Egido J,et a1. Simvastatin inhibits the migration and adhesion of monocytic cells and disorganizes the cytoskeleton of activated endothelial cells. Eur J Pharmacol. 2006 ,24;548(1-3):53-63.
57. Landsberger M, Wolff B, Jantzen F, et a1. Cerivastatin reduces cytokine-induced surface expression of ICAM-1 via increased shedding in human endothelial cells. Atherosclerosis. 2007 ;190(1):43-52.
58. 张新超,徐成斌,王胜洵,普伐他汀对 ApoE 缺陷小鼠主动脉粥样硬化及主动脉壁细胞间黏附分子-1 表达的影响。中华老年医学杂志,2001,20(6)418-420。
59. 杨永宗主编,动脉粥样硬化性心血管病基础与临床,北京:科学出版社,2004,150-151.
60. Asahi M, Huang Z, Thomas S, et a1.Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. J Cereb Blood Flow Metab. 2005;25(6):722-9.
61. Eto M, Rathgeb L, Cosentino F,et a1. Statins blunt thrombin-induced down-regulation of endothelial nitric oxide synthase expression in human endothelial cells. J Cardiovasc Pharmacol. 2006;47(5):663-7.
62. Li JJ, Fang CH, Wang C,et a1. Effects of simvastatin on exercise-induced myocardial ischemia and plasma endothelin-1 concentrations in patients with stable angina. ClinChim Acta. 2005;354(1-2):205-8.
63. Ding QF, Chen ZQ, Yin ZW,et a1. Effects of Zhikeping on aortic oxyradical and the expression of ICAM-1 in a rat model of experimental early atherosclerosis . Zhongguo Zhong Yao Za Zhi. 2006 Mar;31(5):407-10.
64. Alber HF, Frick M, Sussenbacher A, Dorler J, Dichtl W, Stocker EM,Pachinger O, Weidinger F. Effect of atorvastatin on peripheral endothelial function and systemic inflammatory markers in patients with stable coronary artery disease.Wien Med Wochenschr. 2007 Feb;157(3-4):73-78.
65. Marketou ME, Zacharis EA, Nikitovic D,et a1. Early effects of simvastatin versus atorvastatin on oxidative stress and proinflammatory cytokines in hyperlipidemic subjects.Angiology. 2006 Mar-Apr;57(2):211-8.
66. Nachtigal P, Pospisilova N, Pospechova K, et a1. MDOC and atorvastatin have pot -ential antiinflammatory effects in vascular endothelium of ApoE-/- mouse model of atherosclerosis. Life Sci. 2006;78(17):1983-9.
67. Yasuda S, Miyazaki S, Kinoshita H,et a1. Enhanced cardiac production of matrix metalloproteinase-2 and -9 and its attenuation associated with pravastatin treatment in patients with acute myocardial infarction. Clin Sci (Lond). 2007 ;112(1):43-9.
68. Schafer A, Fraccarollo D, Vogt C,et a1.Improved endothelial function and reduced platelet activation by chronic HMG-CoA-reductase inhibition with rosuvastatin in rats with streptozotocin-induced diabetes mellitus. Biochem Pharmacol. 2007 1;73 (9): 1367-75.
69. 叶红; 马万里; 张少华;慢性吸烟大鼠肺组织 FIZZ1/REL Mα 表达的变化中国病理生理杂志,2006,22(5),938-942.
70. Nitenberg A. Hypertension, endothelial dysfunction and cardiovascular risk. Arch Mal Coeur Vaiss. 2006;99(10):915-21.
71. Yamaji-Kegan K, Su Q, Angelini DJ,et a1.Hypoxia-induced mitogenic factor has proangiogenic and proinflammatory effects in the lung via VEGF and VEGF receptor-2. Am J Physiol Lung Cell Mol Physiol. 2006 ;291(6):L1159-68.
72. Lucerna M, Zernecke A, de Nooijer R, et al. endothelial growth factor-A induces plaque expansion in ApoE knock-out mice by promoting de novo leukocyte recruitment. Blood. 2007;109(1):122-9.
1. Holcomb IN, Kabakoff RC, Chan B,et al. Baker TW, FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 2000 ,19(15):4046-4052.
2. Steppan CM, Brown EJ, Wright CM ,et al .A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci U S A. 2001 ,98(2):502-506.
3. Teng X, Li D, Champion HC, Johns RA. FIZZ1/RELMalpha, a novel hypoxia-induced mitogenic factor in lung with vasoconstrictive and angiogenic properties. Circ Res. 2003,92(10):1065-1067.
4. Beltowski J. Adiponectin and resistin--new hormones of white adipose tissue. Med Sci Monit. 2003,9(2):55-61.
5. Gerstmayer B, Kusters D, Gebel S, Muller T, et al.Identification of RELMgamma, a novel resistin-like molecule with a distinct expression pattern. Genomics. 2003, 81 (6):588-595.
6. Blagoev B, Kratchmarova I, Nielsen MM, et al. Inhibition of adipocyte differentiation by resistin-like molecule alpha. Biochemical characterization of its oligomeric nature. J Biol Chem. 2002 ,277(44):42011-42016.
7. Goncharova EA, Ammit AJ, Irani C, et al.PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2002,283(2):354-363.
8. 马万里,叶红,陶晓南 实验性肺纤维化大鼠发病过程中肺组织 FIZZ1 的动态变化 生理学报,2005,57(4):493-497.
9. Misson P, van den Brule S, Barbarin V, et al. Markers of macrophage differentiation in experimental silicosis. J Leukoc Biol. 2004,76(5):926-932.
10. Liu T, Dhanasekaran SM, Jin H, et al.FIZZ1 stimulation of myofibroblast differentiation. Am J Pathol. 2004 ,164(4):1315-1326.
11. Liu T, Jin H, Ullenbruch M, et al. Regulation of found in inflammatory zone 1 expression in bleomycin-induced lung fibrosis: role of IL-4/IL-13 and mediation via STAT-6. J Immunol. 2004,173(5):3425-3431.
12. Stutz AM, Pickart LA, Trifilieff A ,et al.The Th2 cell cytokines IL-4 and IL-13 regulate found in inflammatory zone1/resistin-like molecule alpha gene expression by a STAT6 and CCAAT/enhancer-binding protein-dependent mechanism. J Immunol. 2003,170(4):1789-1796.
13. Li D, Fernandez LG, Dodd-o J, et al. Upregulation of hypoxia-induced mitogenic factor in compensatory lung growth after pneumonectomy. Am J Respir Cell Mol Biol. 2005,32(3):185-191.
14. Wagner KF, Hellberg AK, Balenger S, et al. Hypoxia-induced mitogenic factor has antiapoptotic action and is upregulated in the developing lung: coexpression with hypoxia-inducible factor-2alpha. Am J Respir Cell Mol Biol. 2004,31(3):276-282.
15. Nair MG, Cochrane DW, Allen JE. et al. Macrophages in chronic type 2 inflammation have a novel phenotype characterized by the abundant expression of Ym1 and Fizz1 that can be partly replicated in vitro. Immunol Lett. 2003 ,85(2):173-180.
16. Raes G, Brys L, Dahal BK, et al. Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation.J Leukoc Biol. 2005,77(3):321-327.
17. Noel W, Hassanzadeh G, Raes G, et al.Infection stage-dependent modulation of macrophage activation in Trypanosoma congolense-resistant and -susceptible mice. Infect Immun. 2002,70(11):6180-6187.
18. Nair MG, Gallagher IJ, Taylor MD, et al. Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun. 2005,73(1):385-394.
19. Yamaji-Kegan K, Su Q, Angelini DJ,et a1. Hypoxia-induced mitogenic factor has proangiogenic and proinflammatory effects in the lung via VEGF and VEGF receptor-2. Am J Physiol Lung Cell Mol Physiol. 2006 ;291(6):L1159-68.
20. Tong Q, Zheng L, Lin L,et a1.hypoxia-induced mitogenic factor promotes vascular adhesion molecule-1 expression via the PI-3K/Akt-NF-kappaB signaling pathway.Am J Respir Cell Mol Biol. 2006;35(4):444-56.
1. Holcomb IN, Kabakoff RC, Chan B,et al. Baker TW, FIZZ1, a novel cysteine- rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 2000;19(15):4046-4052.
2. Steppan CM, Brown EJ, Wright CM ,et al .A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci U S A. 2001;98(2):502-506.
3. Gerstmayer B, Kusters D, Gebel S, Muller T, et al.Identification of RELMgamma, a novel resistin-like molecule with a distinct expression pattern. Genomics. 2003; 81 (6):588-595.
4. Liu T, Jin H, Ullenbruch M, et al. Regulation of found in inflammatory zone via STAT-6. J Immunol. 2004;173(5):3425-3431.
5. Teng X, Li D, Champion HC, et al. FIZZ1/RELMalpha, a novel hypoxia-induced mitogenic factor in lung with vasoconstrictive and angiogenic properties. Circ Res. 2003;92(10):1065-1067.
6. Misson P, van den Brule S, Barbarin V, et al. Markers of macrophage differentiation in experimental silicosis. J Leukoc Biol. 2004;76(5):926-932.
7. Li D, Fernandez LG, Dodd-o J, et al. Upregulation of hypoxia-induced mitogenic factor in compensatory lung growth after pneumonectomy. Am J Respir Cell Mol Biol. 2005;32(3):185-191.
8. Nair MG, Gallagher IJ, Taylor MD, et al. Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun. 2005;73(1):385-394.
9. Donnelly S, O'Neill SM, Sekiya M, et al.Thioredoxin peroxidase secreted by Fasciola hepatica induces the alternative activation of macrophages. Infect Immun. 2005;73(1):166-173.
10. Rajala MW, Lin Y, Ranalletta M, et al.Cell type-specific expression and coregulation of murine resistin and resistin-like molecule-alpha in adipose tissue. Mol Endocrinol. 2002 ;16(8):1920-1930.
11. He W, Wang ML, Jiang HQ .Bacterial colonization leads to the colonic secretion of RELMbeta/FIZZ2, a novel goblet cell-specific protein. Gastroenterology. 2003 ; 125(5):1388-1397.
12. Artis D, Wang ML, Keilbaugh SA, et al. RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci U S A. 2004 ;101(37):13596-13600.
13. Banerjee RR, Lazar MA. Dimerization of resistin and resistin-like molecules is determined by a single cysteine. J Biol Chem. 2001;276(28):25970-25973.
14. Kim KH, Lee K, Moon YS, et al. A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. J Biol Chem. 2001;276(14):11252-11256.
15. Yang RZ, Huang Q, Xu A, et al. Comparative studies of resistin expression and phylogenomics in human and mouse. Biochem Biophys Res Commun. 2003 ; 310(3):927-935.
16. Morash BA, Willkinson D, Ur E, et al. Resistin expression and regulation in mouse pituitary. FEBS Lett. 2002;526(1-3):26-30.
17. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409(6818):307-312.
18. Nagaev I, Smith U. Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem Biophys Res Commun. 2001;285(2):561-564.
19. Utzschneider KM, Carr DB, Tong J, et al. Resistin is not associated with insulin sensitivity or the metabolic syndrome in humans. Diabetologia. 2005;48 (11): 2330-3.
20. 许莉军,张木勋 Resistin 与胰岛素抵抗 .中国微循环 2004;8(1):286-289。
21. Shojima N, Sakoda H, Ogihara T, et al.Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes. 2002 ;51(6):1737-1744.
22. Schinke T, Haberland M, Jamshidi A. Cloning and functional characterization of resistin-like molecule gamma. Biochem Biophys Res Commun. 2004 ;314 (2): 356-362.
23. Shojima N, Ogihara T, Inukai K.et al. Serum concentrations of resistin-like molecules beta and gamma are elevated in high-fat-fed and obese db/db mice, with increased production in the intestinal tract and bone marrow.Diabetologia. 2005; 48 (5): 984-992.
24. Kushiyama A, Shojima N, Ogihara T, et al. Resistin like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes and induces diabetes.J Biol Chem.2005;280(51):42016-25.
25. 陈江,洪雪,马志兰. 尿内皮素在糖尿病患者肾脏微血管早期损害的诊断价值.中国微循环.2004;8(5):60-63.
26. Reilly MP, Lehrke M, Wolfe ML, et al. Resistin is an inflammatory marker of atherosclerosis in humans. Circulation. 2005;111(7):932-939.
27. Burnett MS, Devaney JM, Adenika RJ, et al. Cross Sectional Associations of Resistin, Coronary Heart Disease and Insulin Resistance. J Clin Endocrinol Metab. 2006;91(1):64-8.
28. 章建梁 秦永文 郑 兴等。 血清抵抗素浓度与血压的相关性研究.解放军医学杂志 2003;28(3):241-245.
29. 毛红仙 汪大望 郑景晨等。血浆抵抗素与 2 型糖尿病的相关性. 中华糖尿病杂志 2005 ;13(4):274-276.
1. Holcomb IN, Kabakoff RC, Chan B,et al. Baker TW, FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 2000 ,19:4046-4052.
2. Steppan CM, Brown EJ, Wright CM ,et al .A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci U S A. 2001 ,98:502-506.
3. Gerstmayer B, Kusters D, Gebel S, Muller T, et al.Identification of RELMgamma, a novel resistin-like molecule with a distinct expression pattern. Genomics. 2003, 81: 588-595.
4. Beltowski J. Adiponectin and resistin--new hormones of white adipose tissue. Med Sci Monit. 2003,9:RA55-61.
5. Blagoev B, Kratchmarova I, Nielsen MM, et al. Inhibition of adipocyte differentiation by resistin-like molecule alpha. Biochemical characterization of its oligomeric nature. J Biol Chem. 2002 ,277:42011-42016.
6. Teng X, Li D, Champion HC, Johns RA. FIZZ1/RELMalpha, a novel hypoxia-induced mitogenic factor in lung with vasoconstrictive and angiogenic properties. Circ Res. 2003,92:1065-1067.
7. Goncharova EA, Ammit AJ, Irani C, et al.PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2002,283:L354-363.
8. Liu T, Jin H, Ullenbruch M, et al. Regulation of found in inflammatory zone 1 expression in bleomycin-induced lung fibrosis: role of IL-4/IL-13 and mediation via STAT-6. J Immunol. 2004 ,173:3425-3431.
9. Stutz AM, Pickart LA, Trifilieff A ,et al.The Th2 cell cytokines IL-4 and IL-13 regulate found in inflammatory zone1/resistin-like molecule alpha gene expression by a STAT6 and CCAAT/enhancer-binding protein-dependent mechanism. J Immunol. 2003, 170: 1789-1796.
10. Nair MG, Cochrane DW, Allen JE. et al. Macrophages in chronic type 2 inflammation have a novel phenotype characterized by the abundant expression of Ym1 and Fizz1 that can be partly replicated in vitro. Immunol Lett. 2003 ,85(2):173-180.
11. Nair MG, Gallagher IJ, Taylor MD, et al. Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun. 2005,73(1):385-394.
12. Donnelly S, O'Neill SM, Sekiya M, et al.Thioredoxin peroxidase secreted by Fasciola hepatica induces the alternative activation of macrophages. Infect Immun. 2005, 73 (1):166-173.
13. Raes G, Brys L, Dahal BK, et al. Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation.J Leukoc Biol. 2005,77(3):321-327.
14. Raes G, De Baetselier P, Noel W, et al, Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages. J Leukoc Biol. 2002 ,71 (4): 597-602.
15. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003 ,3(1):23-35.
16. Rajala MW, Lin Y, Ranalletta M, et al.Cell type-specific expression and coregulation of murine resistin and resistin-like molecule-alpha in adipose tissue. Mol Endocrinol. 2002 ;16(8):1920-30.
17. Misson P, van den Brule S, Barbarin V, et al. Markers of macrophage differentiation in experimental silicosis. J Leukoc Biol. 2004,76:926-932.
18. Shojima N, Sakoda H, Ogihara T, et al. Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes. 2002;51(6):1737-44.
19. Li D, Fernandez LG, Dodd-o J, et al. Upregulation of hypoxia-induced mitogenic factor in compensatory lung growth after pneumonectomy. Am J Respir Cell Mol Biol. 2005,32(3):185-91.
20. Liu T, Dhanasekaran SM, Jin H, et al. FIZZ1 stimulation of myofibroblast different -tiation. Am J Pathol. 2004 ,164:1315-1326.
21. Tong Q, Zheng L, Lin L,et a1.hypoxia-induced mitogenic factor promotes vascular adhesion molecule-1 expression via the PI-3K/Akt-NF-kappaB signaling pathway.Am J Respir Cell Mol Biol. 2006;35(4):444-56.