罗格列酮对高糖诱导大鼠胸主动脉平滑肌细胞增殖和凋亡的影响
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摘要
目的:血管并发症是糖尿病(diabetes melletus, DM)患者致死的首要原因,动脉粥样硬化(atherosclerosis, AS)与DM共存。DM患者血糖控制不理想与微血管和大血管病变紧密相关,高血糖在DM血管并发症的发展过程中起着主要作用。血管平滑肌细胞(vascular smooth muscle cells,VSMCs)的过量增生是AS的一个主要特征。已证实,细胞增生是内膜增厚的基本特征之一,但现在普遍认为细胞凋亡调节的紊乱也同样重要。AS中VSMCs的大量聚集是细胞高度增生和凋亡减少共同作用的结果。许多研究证实,高浓度葡萄糖可促进AS的发展,增加体外VSMCs的生长率。高糖不仅能显著抑制无血清诱导的体外培养大鼠VSMCs的凋亡,还能增强抗凋亡蛋白Bcl-2和Bcl-xl的表达,此外明显降低人冠状动脉平滑肌细胞的DNA断裂率。过氧化物酶体增殖物激活受体γ(Peroxisome Proliferator-Activated Receptorsγ, PPARγ)是核受体超家族的一个转录因子。PPARγ在VSMCs有表达,在机械损伤的动脉壁中表达显著上调。罗格列酮(rosiglitazone, RSG)属于噻唑烷类二酮药物(thiazolidinediones, TZDs),为PPARγ人工合成配体,是临床上用于治疗DM的胰岛素增敏剂。许多资料显示,TZDs还可延缓AS进程。RSG可减少颈总动脉内膜-中层厚度(IMT),而后者是冠状AS的预测指标。RSG还可减少DM小鼠的动脉粥样斑块总面积并抑制斑块中巨噬细胞的聚集。在离体实验中,RSG可抑制人VCSMs增殖并促进其凋亡,但对于高糖诱导的VCSMs增殖、凋亡及其相关分子机制的影响鲜有报道。本实验通过原代培养大鼠胸主动脉VSMCs,研究RSG对高浓度葡萄糖孵育下的VSMCs增殖、凋亡以及Bcl-2、Bcl-xl的影响,探讨RSG对AS的作用机制。
方法:1运用改良组织贴块法进行大鼠胸主动脉VSMCs原代培养并传代,应用自然纯化方法纯化细胞,根据细胞形态学特点和α-actin免疫细胞化学染色进行细胞鉴定;
2取处于对数生长期的第5~6代细胞,用MTT法检测不同浓度RSG对高糖孵育下细胞增殖活性的影响;
3取处于对数生长期的第5~6代细胞,流式细胞术检测RSG对高糖孵育下细胞周期、凋亡率及Bcl-2、Bcl-xl蛋白表达的影响;
4取处于对数生长期的第5~6代细胞,Western blot技术检测RSG对高糖孵育下细胞Bcl-2、Bcl-xl蛋白表达的影响。
结果:1原代培养时,约80%的组织块接种成活,培养细胞呈典型的“谷峰状”生长,经平滑肌细胞特异的α-actin免疫化学染色后,培养细胞的胞浆着色呈阳性反应;
2用MTT法检测VSMCs的增殖活性,发现在高浓度葡萄糖诱导下,VSMCs显著增殖(P<0.05),而高渗组细胞的增殖能力没有明显改变; RSG(30、100μmol/L)可抑制高浓度葡萄糖诱导的VSMCs的增殖(P<0.05),且呈剂量依赖性;用RSG拮抗剂GW9662(10μmol/L)预处理后,RSG的抑制作用部分被拮抗;
3用流式细胞仪检测细胞各周期的时相分布,显示高浓度葡萄糖可诱导G0/G1期细胞可向S期转化,而高渗组对细胞各周期均没有影响;RSG可抑制高糖诱导的G0/G1→S,G0/G1期细胞数目明显增多,S期细胞数目减少(P<0.05);GW9662可部分逆转RSG的抑制作用;
4用流式细胞仪检测凋亡率及Bcl-2、Bcl-xl蛋白表达量,发现高浓度葡萄糖能显著降低VSMCs的凋亡率,Bcl-2和Bcl-xl蛋白表达均增强(P<0.05),而高渗组对细胞凋亡率及Bcl-2、Bcl-xl蛋白表达量均无影响;RSG(30、100μmol/L)能够促进高糖组VSMCs的凋亡,Bcl-2、Bcl-xl蛋白表达量显著减少,且呈浓度依赖性;拮抗剂GW9662能部分拮抗RSG的促凋亡作用;
5 Western blot技术检测RSG对VSMCs Bcl-2、Bcl-xl蛋白表达量的影响,结果显示高浓度葡萄糖能使bcl-xl蛋白的表达明显增强,且糖浓度越高蛋白表达越强,而高渗组对Bcl-xl蛋白表达没有影响;RSG(30、100μmol/L)能显著降低高糖组Bcl-xl蛋白的表达量,且呈浓度依赖性;用GW9662预处理后,Bcl-xl蛋白的表达量又显著上升。Bcl-2蛋白未测出。
结论:1高浓度葡萄糖能促进VSMCs增殖,显著降低VSMCs的凋亡凋亡率,增强Bcl-xl、Bcl-2的蛋白表达量;而高渗组对细胞没有影响。提示高糖状态可能是糖尿病动脉粥样硬化发生机制之一。
2 30～100μmol/L的RSG均能在体外有效抑制高糖孵育的VSMCs由G0/G1期向S期的转变,降低高糖组VSMCs内抗凋亡蛋白Bcl-xl、Bcl-2的表达,促进其凋亡,呈剂量依赖性。提示RSG可能通过对高糖诱导的VSMCs增殖和凋亡机制的干预,对T2DM血管病变起到了保护作用。
Objective: Vascular complications are the leading cause of death in diabetic patients, atherosclerosis is accelerated by the coexistence of diabetes mellitus. Poor control of diabetes is associated with the development of micro- and macroangiopathy, hyperglycemia in diabetic patients is believed to play a major role in the development of these vascular complications. Increased proliferation of vascular smooth muscle cells (VSMCs) is a key feature in the atherosclerotic lesion. It is well established that cell growth is a fundamental feature of intimal hyperplasia, and it is widely accepted that perturbations in the regulation of apoptosis are equally important. Excessive accumulation of VSMCs in atherosclerosis suggests reduced apoptosis and excessive cell proliferation in the lesions. Several findings support the concept that hyperglycemia accelerates the development of atherosclerosis. High concentration of glucose enhances growth rate in cultured VSMCs. Treatment with a high glucose not only significantly attenuate apoptosis in response to serum withdrawal in cultured rat VSMCs, but also markedly increased the expression of Bcl-2 and Bcl-xl. Another reports shows that there was a significant decrease in the DNA fragmentation ratio of human coronary artery smooth muscle cells cultured at high glucose concentration. Peroxisome proliferator-activated receptor (PPARγ) is a transcription factor belonging to the nuclear hormone receptor gene super-family. PPARγis expressed in VSMCs and prominently upregulated in response to mechanical injury of the arterial wall. Thiazolidinediones (TZDs) are synthetic ligands for PPARγand are commonly used as insulin-sensitizing agents in the treatment of type 2 diabetes. Data suggest that TZDs may also retard atherosclerotic disease progression. Treatment with rosiglitazone (RSG) decreased mean common carotid artery (CCA) intima-media thickness (IMT) progression, a surrogate index of atherosclerotic disease progression. Rosiglitazone attenuated total plaque area in diabetic mice and suppressd macrophage accumulation in diabetic aortic plaques. Although some reports indicated that RSG can inhibit cell proliferation and promote apoptosis in human VSMCs in vitro, little is known about the effect of rosiglitazone on proliferation and apoptosis and its related mechanisms of VSMCs treated with high glucose. To elucidate the precise mechanisms of RSG on AS, the effect of RSG on VSMCs proliferation, apoptosis and expression of Bcl-2, Bcl-xl in rat thoractic aorta smooth muscle cells were examined.
Methods: 1 The primary and transfer culture were done by modified tissue-piece inoculation and trypsin digestion respectively. The cells were purified by natural passage transfer. The cultured cells were identified by morphological characteristics and immunocytochemistry with antibody toα-actin.
2 The fifth to sixth passage purified cells were harvested for the following experiment. The effect of RSG on the cell proliferating viability in high concentration glucose was observed by MTT assay.
3 The fifth to sixth passage purified cells were harvested for the following experiment. Flow cytometry was preformed to analyze the influences of RSG on cell cycle distribution, apoptosis rate and Bcl-2, Bcl-xl expression in high concentration glucose.
4 The fifth to sixth passage purified cells were harvested for the following experiment. The effect of RSG on Bcl-2, Bcl-xl expression in VSMCs incubated in high concentration glucose was detected by Western blot.
Results: 1 Approximately 80% inoculated tissue pieces survived in primary culture. The cultured cells possessed“peak and valley”characteristics for VSMCs Immunocytochemical staining with specific antibody against SM-α-actin demonstrated these cells were positive.
2 MTT assays were used to characterize the viability of VSMCs. The proliferating viability of VSMCs induced by high concentration glucose was remarkably increased when compared with the normal glucose group (P<0.05) , and treatment of the cells with mannitol, used as an osmotic control, had no significant effect on apoptosis in rat VSMCs; RSG(30、100μmol/L)can inhibited the proliferation of VSMCs by high glucose treatment (P<0.05), and displayed in concention-dependent; the effects of RSG was attenuated partly after pretreated with GW9662 (10μmol/L).
3 To detect the cell cycle progression of VSMCs, flow cytometric analysis was performed. High glucose can induce cell cycle progression from G0/G1 phase to S phase, and the cell cycle progression was not altered by mannitol treatment compared with the control; RSG (30～100μmol/L) pretreated for 48h can inhibit VSMCs cell cycle progression from G0/G1 phase to S phase, the cell number significantly decreased in G0/G1 phase and increased in S phase(P<0.05); GW9662 can suppress the function of RSG.
4 We used flow cytometric analysis to determine the apoptosis rate and Bcl-2, Bcl-xl expression in VSMCs. Treatment with a high glucose significantly attenuated apoptosis rate and increased expression of Bcl-2 and Bcl-xl protein in cultured rat VSMCs when compared with the normal glucose group(P<0.05), but the mannitol have no effect on apoptosis rate and expression of Bcl-2 and Bcl-xl protein; Treatment with RSG(30、100μmol/L) can promoted apoptosis of VSMCs and reduced expression of Bcl-2 and Bcl-xl protein in high glucose group in a dose-dependent manner; the effect of proapoptosis can be suppressed partly by GW9662.
5 Western blot demonstrated that high glucose upregulated Bcl-xL protein and depended in glucose concentration, and expression of Bcl-xl protein had no change when treated with mannitol; the expression of Bcl-xl protein induced by high glucose was decreased by RSG (30、100μmol/L) and increased when pretreated with GW9662. However, Bcl-2 was not detected in VSMCs.
Conclusions: 1 High glucose can induce the proliferation and inhibit apoptosis by increasing the expression of Bcl-xl and Bcl-2 protein in rat VSMCs; treatment with mannitol had no effect on VSMCs, indicating that high glucose condition may represent one of the mechanisms for atherosclerosis observed in T2DM.
2 RSG (30～100μmol/L) can inhibit VSMCs cell cycle progression from G0/G1 phase to S phase, decrease expression of Bcl-2, Bcl-xl protein and promote VSMCs to apoptosis induced by high glucose in cultured VSMCs. These finding suggested that RSG may play a protective role against diabetic angiopathy through the intervention of proliferation and apoptosis in VSMCs.
方法:1运用改良组织贴块法进行大鼠胸主动脉VSMCs原代培养并传代,应用自然纯化方法纯化细胞,根据细胞形态学特点和α-actin免疫细胞化学染色进行细胞鉴定;
2取处于对数生长期的第5~6代细胞,用MTT法检测不同浓度RSG对高糖孵育下细胞增殖活性的影响;
3取处于对数生长期的第5~6代细胞,流式细胞术检测RSG对高糖孵育下细胞周期、凋亡率及Bcl-2、Bcl-xl蛋白表达的影响;
4取处于对数生长期的第5~6代细胞,Western blot技术检测RSG对高糖孵育下细胞Bcl-2、Bcl-xl蛋白表达的影响。
结果:1原代培养时,约80%的组织块接种成活,培养细胞呈典型的“谷峰状”生长,经平滑肌细胞特异的α-actin免疫化学染色后,培养细胞的胞浆着色呈阳性反应;
2用MTT法检测VSMCs的增殖活性,发现在高浓度葡萄糖诱导下,VSMCs显著增殖(P<0.05),而高渗组细胞的增殖能力没有明显改变; RSG(30、100μmol/L)可抑制高浓度葡萄糖诱导的VSMCs的增殖(P<0.05),且呈剂量依赖性;用RSG拮抗剂GW9662(10μmol/L)预处理后,RSG的抑制作用部分被拮抗;
3用流式细胞仪检测细胞各周期的时相分布,显示高浓度葡萄糖可诱导G0/G1期细胞可向S期转化,而高渗组对细胞各周期均没有影响;RSG可抑制高糖诱导的G0/G1→S,G0/G1期细胞数目明显增多,S期细胞数目减少(P<0.05);GW9662可部分逆转RSG的抑制作用;
4用流式细胞仪检测凋亡率及Bcl-2、Bcl-xl蛋白表达量,发现高浓度葡萄糖能显著降低VSMCs的凋亡率,Bcl-2和Bcl-xl蛋白表达均增强(P<0.05),而高渗组对细胞凋亡率及Bcl-2、Bcl-xl蛋白表达量均无影响;RSG(30、100μmol/L)能够促进高糖组VSMCs的凋亡,Bcl-2、Bcl-xl蛋白表达量显著减少,且呈浓度依赖性;拮抗剂GW9662能部分拮抗RSG的促凋亡作用;
5 Western blot技术检测RSG对VSMCs Bcl-2、Bcl-xl蛋白表达量的影响,结果显示高浓度葡萄糖能使bcl-xl蛋白的表达明显增强,且糖浓度越高蛋白表达越强,而高渗组对Bcl-xl蛋白表达没有影响;RSG(30、100μmol/L)能显著降低高糖组Bcl-xl蛋白的表达量,且呈浓度依赖性;用GW9662预处理后,Bcl-xl蛋白的表达量又显著上升。Bcl-2蛋白未测出。
结论:1高浓度葡萄糖能促进VSMCs增殖,显著降低VSMCs的凋亡凋亡率,增强Bcl-xl、Bcl-2的蛋白表达量;而高渗组对细胞没有影响。提示高糖状态可能是糖尿病动脉粥样硬化发生机制之一。
2 30～100μmol/L的RSG均能在体外有效抑制高糖孵育的VSMCs由G0/G1期向S期的转变,降低高糖组VSMCs内抗凋亡蛋白Bcl-xl、Bcl-2的表达,促进其凋亡,呈剂量依赖性。提示RSG可能通过对高糖诱导的VSMCs增殖和凋亡机制的干预,对T2DM血管病变起到了保护作用。
Objective: Vascular complications are the leading cause of death in diabetic patients, atherosclerosis is accelerated by the coexistence of diabetes mellitus. Poor control of diabetes is associated with the development of micro- and macroangiopathy, hyperglycemia in diabetic patients is believed to play a major role in the development of these vascular complications. Increased proliferation of vascular smooth muscle cells (VSMCs) is a key feature in the atherosclerotic lesion. It is well established that cell growth is a fundamental feature of intimal hyperplasia, and it is widely accepted that perturbations in the regulation of apoptosis are equally important. Excessive accumulation of VSMCs in atherosclerosis suggests reduced apoptosis and excessive cell proliferation in the lesions. Several findings support the concept that hyperglycemia accelerates the development of atherosclerosis. High concentration of glucose enhances growth rate in cultured VSMCs. Treatment with a high glucose not only significantly attenuate apoptosis in response to serum withdrawal in cultured rat VSMCs, but also markedly increased the expression of Bcl-2 and Bcl-xl. Another reports shows that there was a significant decrease in the DNA fragmentation ratio of human coronary artery smooth muscle cells cultured at high glucose concentration. Peroxisome proliferator-activated receptor (PPARγ) is a transcription factor belonging to the nuclear hormone receptor gene super-family. PPARγis expressed in VSMCs and prominently upregulated in response to mechanical injury of the arterial wall. Thiazolidinediones (TZDs) are synthetic ligands for PPARγand are commonly used as insulin-sensitizing agents in the treatment of type 2 diabetes. Data suggest that TZDs may also retard atherosclerotic disease progression. Treatment with rosiglitazone (RSG) decreased mean common carotid artery (CCA) intima-media thickness (IMT) progression, a surrogate index of atherosclerotic disease progression. Rosiglitazone attenuated total plaque area in diabetic mice and suppressd macrophage accumulation in diabetic aortic plaques. Although some reports indicated that RSG can inhibit cell proliferation and promote apoptosis in human VSMCs in vitro, little is known about the effect of rosiglitazone on proliferation and apoptosis and its related mechanisms of VSMCs treated with high glucose. To elucidate the precise mechanisms of RSG on AS, the effect of RSG on VSMCs proliferation, apoptosis and expression of Bcl-2, Bcl-xl in rat thoractic aorta smooth muscle cells were examined.
Methods: 1 The primary and transfer culture were done by modified tissue-piece inoculation and trypsin digestion respectively. The cells were purified by natural passage transfer. The cultured cells were identified by morphological characteristics and immunocytochemistry with antibody toα-actin.
2 The fifth to sixth passage purified cells were harvested for the following experiment. The effect of RSG on the cell proliferating viability in high concentration glucose was observed by MTT assay.
3 The fifth to sixth passage purified cells were harvested for the following experiment. Flow cytometry was preformed to analyze the influences of RSG on cell cycle distribution, apoptosis rate and Bcl-2, Bcl-xl expression in high concentration glucose.
4 The fifth to sixth passage purified cells were harvested for the following experiment. The effect of RSG on Bcl-2, Bcl-xl expression in VSMCs incubated in high concentration glucose was detected by Western blot.
Results: 1 Approximately 80% inoculated tissue pieces survived in primary culture. The cultured cells possessed“peak and valley”characteristics for VSMCs Immunocytochemical staining with specific antibody against SM-α-actin demonstrated these cells were positive.
2 MTT assays were used to characterize the viability of VSMCs. The proliferating viability of VSMCs induced by high concentration glucose was remarkably increased when compared with the normal glucose group (P<0.05) , and treatment of the cells with mannitol, used as an osmotic control, had no significant effect on apoptosis in rat VSMCs; RSG(30、100μmol/L)can inhibited the proliferation of VSMCs by high glucose treatment (P<0.05), and displayed in concention-dependent; the effects of RSG was attenuated partly after pretreated with GW9662 (10μmol/L).
3 To detect the cell cycle progression of VSMCs, flow cytometric analysis was performed. High glucose can induce cell cycle progression from G0/G1 phase to S phase, and the cell cycle progression was not altered by mannitol treatment compared with the control; RSG (30～100μmol/L) pretreated for 48h can inhibit VSMCs cell cycle progression from G0/G1 phase to S phase, the cell number significantly decreased in G0/G1 phase and increased in S phase(P<0.05); GW9662 can suppress the function of RSG.
4 We used flow cytometric analysis to determine the apoptosis rate and Bcl-2, Bcl-xl expression in VSMCs. Treatment with a high glucose significantly attenuated apoptosis rate and increased expression of Bcl-2 and Bcl-xl protein in cultured rat VSMCs when compared with the normal glucose group(P<0.05), but the mannitol have no effect on apoptosis rate and expression of Bcl-2 and Bcl-xl protein; Treatment with RSG(30、100μmol/L) can promoted apoptosis of VSMCs and reduced expression of Bcl-2 and Bcl-xl protein in high glucose group in a dose-dependent manner; the effect of proapoptosis can be suppressed partly by GW9662.
5 Western blot demonstrated that high glucose upregulated Bcl-xL protein and depended in glucose concentration, and expression of Bcl-xl protein had no change when treated with mannitol; the expression of Bcl-xl protein induced by high glucose was decreased by RSG (30、100μmol/L) and increased when pretreated with GW9662. However, Bcl-2 was not detected in VSMCs.
Conclusions: 1 High glucose can induce the proliferation and inhibit apoptosis by increasing the expression of Bcl-xl and Bcl-2 protein in rat VSMCs; treatment with mannitol had no effect on VSMCs, indicating that high glucose condition may represent one of the mechanisms for atherosclerosis observed in T2DM.
2 RSG (30～100μmol/L) can inhibit VSMCs cell cycle progression from G0/G1 phase to S phase, decrease expression of Bcl-2, Bcl-xl protein and promote VSMCs to apoptosis induced by high glucose in cultured VSMCs. These finding suggested that RSG may play a protective role against diabetic angiopathy through the intervention of proliferation and apoptosis in VSMCs.
引文
1 Ruiz E, Gordillo-Moscoso A, Padilla E, et al. Human vascular smooth muscle cells from diabetic patients are resistant to induced apoptosis due to high Bcl-2 expression. Diabetes, 2006, 55: 1243-1251
2 Wakino S, Kintscher U, Kim S, et al. Peroxisome proliferator-activated receptor gamma ligands inhibit retinoblastoma phosphorylation and G13S transition in vascular smooth muscle cells. J Biol Chem, 2000, 275: 22435-22441
3 Bruemmer D, Yin F, Liu J, et al. Peroxisome proliferator-activated receptor γ inhibits expression of minichromosome maintenance proteins in vascular smooth muscle cells. Mol Endocrinol, 2003, 17: 1005-1018
4 Bruemmer D, Yin F, Liu J, et al. Regulation of the growth arrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor γ in vascular smooth muscle cells. Circ Res, 2003, 93: 38-47
5 Sidhu JS, Kaposzta Z, Markus HS, et al. Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patients without diabetes mellitus. Arterioscler Thromb Vasc Biol, 2004, 24: 930-934
6 Tikellis C, Jandeleit-Dahm KA, Sheehy K, et al. Reduced plaque formation induced by rosiglitazone in anSTZ-diabetes mouse model of atherosclerosis is associated with downregulation of adhesion molecules. Elsevier Ireland Ltd, 2007, 10: 38-48
7 Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med, 1999, 340: 115-126
8 Wilson PWF, Cupples LA, Kannel WB. Is hyperglycemia associated with cardiovascular disease? The Framingham Study. Am Heart J, 1991, 121: 586-590
9 Li H, Te′ le′maque S, Miller RE, et al. High glucose inhibits apoptosis induced by serum deprivation in vascular smooth muscle cells via upregulation of Bcl-2 and Bcl-xl. Diabetes, 2005, 54: 540-545
10 Marx N, Schonbeck U, Lazar MA, et al. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res, 1998, 83: 1097-1103
11 Ricote M, Li AC, Willson TM, et al. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature, 1998, 391: 79-82
12 Ronald E, Goetze S, Xi XP, et al. Expression and function of PPAR γ in rat and human vascular smooth muscle cells. Circulation, 2000, 101: 1311-1318
13 Guan Y. Targeting peroxisome proliferators-activated receptors (PPARs) in kidney and urologic disease. Minerva Urol Nefrol, 2002, 54: 65-79
14 Guan Y, Zhang Y, Breyer MD. The role of PPARs in the transcriptional control of cellular processes. Drug News Perspect, 2002, 15: 147-154
15 Ricote M, Huang J, Fajas L, et al. Expression of the peroxisome proliferator-activated receptor (PPAR) in human atherosclerosis and regulation in macrophages by colony-stimulating factors and oxidized low-density lipoprotein. Proc Natl Acad Sci, 1998, 95(13): 7614-7619
16 de Dios ST, Hannan KM, Dilley RJ, et al. Troglitazone, but not rosiglitazone, inhibits Na/H exchange activity and proliferation of macrovascular endothelial cells. J Diabetes Complications, 2001, 15(3): 120-127
17 Masamune A, Kikuta K, Satoh M, et al. Ligands of peroxisome proliferator-activated receptor-gamma block activation of pancreatic stellate cells. J Biol Chem, 2002, 277(1): 141-147
18 Galli A, Crabb D, Price D, et al. Peroxisome proliferator-activated receptor gamma transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells. Hepatology, 2000, 31(1): 101-108
19 Hayon T, Dvilansky A, Shpilberg O, et al. Appraisal of the MTT-based assay as a useful tool for predicting drug chemosensitivity in leukemia. Leuk Lymphoma, 2003, 44(11): 1957-1962
20 MacCorkle RA, Tan TH. Mitogen-activated protein kinasesin cell-cycle control. Cell Biochem Biophys, 2005, 43(3): 451-461
21 Yamamoto M, Acevedo-Duncan M, Chalfant CE, et al. Acute glucose-induced downregulation of PKC-II accelerates cultured VSMC proliferation. Am J Physiol Cell Physiol, 2000, 279: 587-595
22 de Dios ST, Bruemmer D, Dilley TJ, et a1. Inhibitory acitivty of clinical htiazolidindeione peorxicsme porliferator acivating receptor-gamma ligands toward internal mammary artery, radial artery, and saphenous vein smooth muscle cell proliferation [J]. Ciroulation, 2003, 27: 2548-2550
1 Bochaton-Piallat ML, Gabbiani F, Redard M, et al. Apoptosis participates in cellularity regulation during rat aortic intimal thickening. Am J Pathol, 1995, 146: 1059-1064
2 Han DK, Haudenschild CC, Hong MK, et al. Evidence for apoptosis in human atherogenesis and in a rat vascular injury model. Am J Pathol, 1995, 147: 267-277
3 Pollman MJ, Hall JL, Mann MJ, et al. Inhibition of neointimal cell bcl-x expression induces apoptosis and regression of vascular disease. Nat Med, 1998, 4: 222-227
4 Haikun Li, Sabine Te′ le′maque, Richard E. Miller, et al. High glucose inhibits apoptosis induced by serum deprivation in vascular smooth muscle cells via upregulation of Bcl-2 and Bcl-xl. Diabetes, 2005, 54: 540-545
5 Bruemmer D, Yin F, Liu J, et al. Regulation of the growtharrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor γ in vascular smooth muscle cells. Circ Res, 2003, 93: 38-47
6 Law RE, Goetz S, Xi XP, et al. Expression and function of PPAR- γ in rat and human vascular smooth muscle cells. Circulation, 2000, 101(11): 1311-1318
7 Ricote M, Huang J, Fajas L, et al. Expression of the peroxisome proliferator-activated receptor (PPAR) in human atherosclerosis and regulation in macrophages by colony-stimulating factors and oxidized low-density lipoprotein. Proc Natl Acad Sci, 1998, 95(13): 7614-7619
8 Kockx MM, Knaapen MW. The role of apoptosis in vascular disease. J Pathol, 2000, 190: 267-280
9 Perlman H, Sata M, Krasinski K, et al. Adenovirusencoded hammerhead ribozyme to Bcl-2 inhibits neointimal hyperplasia and induces vascular smooth muscle cell apoptosis. Cardiovasc Res, 2000, 45: 570-578
10 Chinnaiyan AM, O’Rourke K, Lane BR, et al. Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death. Science, 1997, 275: 1122-1126
11 Decaudin D, Geley S, Hirsch T, et al. Bcl-2 and Bcl-XL antagonize the mitochondrial dysfunction preceding nuclear apoptosis induced by chemotherapeutic agents. Cancer Res, 1997, 57: 62- 67
12 Kharbanda S, Pandey P, Schofield L, et al. Role of Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis. Proc Natl Acad Sci USA, 1997, 94: 6939-6942
13 Leesnitzer LM, Parks DJ, Bledsoe RK, et al. Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry, 2002, 41: 6640-6650
1 Guan Y. Targeting Peroxisome proliferators-activated receptors (PPARs) in kidney and urologic disease. Minerva Urol Nefrol, 2002, 54:65-79
2 Guan Y, Zhang Y, Breyer MD. The role of PPARs in the transcriptional control of cellular processes. Drug News Perspect, 2002, 15: 147-154
3 Law RE, Goetze S, Xi XP, et al. Expression and function of PPARγ in rat and human vascular smooth muscle cells. Circulation, 2000, 101: 1311-1318
4 Ajjan R, Grant PJ. Coagulation and atherothrombotic disease. Atherosclerosis, 2006, 186:240-259
5 Madamanchi NR, Hakim ZS, Runge MS. Oxidative stress in atherogenesis and arterial thrombosis: the disconnect between cellular studies and clinical outcomes. J Thromb Haemost 2005, 3: 254-267
6 Newby AC. Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev, 2005, 85: 1-31
7 Rosenson RS, Koenig W. Utility of inflammatory markers inthe management of coronary artery disease. Am J Cardiol, 2003, 92: 10-18
8 Libby P, Ridker PM. Inflammation and atherosclerosis: role of C-reactive protein in risk assessment. Am J Med, 2004, 116(suppl 6A): 9-16
9 Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev, 1995, 75: 473-486
10 Reaven G. Syndrome X. Curr Treat Options Cardiovasc Med, 2001, 3: 323-332
11 Haffner SM, D'Agostino R Jr, Mykkanen L, et al. Insulin sensitivity in subjects with type 2 diabetes. Relationship to cardiovascular risk factors: the Insulin Resistance Atherosclerosis Study. Diabetes Care, 1999, 22:562-568
12 Henry RR. Insulin resistance: from predisposing factor to therapeutic target in type 2 diabetes. Clin Ther, 2003, 25: 47-63
13 Stolar MW, Chilton RJ. Type 2 diabetes, cardiovascular risk, and the link to insulin resistance. Clin Ther, 2003, 25: 4-31
14 Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomized placebo-controlled trial. Lancet, 2004, 364: 685-696
15 Betteridge DJ. Long-term risk reduction: who needs treatment? Diabetes Res Clin Pract, 2005, 68: 15-22
16 Ginsberg HN. Review: Efficacy and mechanisms of actionof statins in the treatment of diabetic dyslipidemia. J Clin Endocrinol Metab, 2006, 91: 383-392
17 JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart, 2005, 91(suppl 5): 1-52
18 Faergeman O. Hypertriglyceridemia and the fibrate trials. Curr Opin Lipidol, 2000, 11: 609-614
19 Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet, 2005, 366: 1849-1861
20 Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA, 1979, 241: 2035-2038
21 Kannel WB. Overview of hemostatic factors involved in atherosclerotic cardiovascular disease. Lipids, 2005, 40: 1215-122.
22 Stamler J, Vaccaro O, Neaton JD, et al.. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care, 1993, 16: 434-444
23 Adler AI, Stratton IM, Neil HA et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ, 2000, 321: 412-419
24 Mogensen CE, Chachati A, Christensen CK, et al.Microalbuminuria: an early marker of renal involvement in diabetes. Uremia Invest, 1985, 9: 85-95
25 Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA, 2001, 286: 421-426
26 Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, et al. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation, 2004, 110: 32-35
27 Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, et al. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia, 1989, 32: 219-226
28 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science, 1993, 259: 87-91
29 Dandona P, Weinstock R, Thusu K, et al. Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab, 1998, 83: 2907-2910
30 Yudkin JS, Stehouwer CD, Emeis JJ, et al. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol, 1999, 19: 972-978
31 Pickup JC, Mattock MB, Chusney GD, et al. NIDDM as a disease of the innate immune system: association ofacute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia, 1997, 40: 1286-1292
32 Blankenberg S, Rupprecht HJ, Bickel C, et al. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation, 2001, 104: 1336-1342
33 Esposito K, Nappo F, Giugliano F, et al. Cytokine milieu tends toward inflammation in type 2 diabetes. Diabetes Care, 2003, 26: 1647
34 Lee SW, Song KE, Shin DS, et al. Alterations in peripheral blood levels of TIMP-1, MMP-2, and MMP-9 in patients with type-2 diabetes. Diabetes Res Clin Pract, 2005, 69: 175-179
35 Boemi M, Leviev I, Sirolla C, et al. Serum paraoxonase is reduced in type 1 diabetic patients compared to nondiabetic, first degree relatives; influence on the ability of HDL to protect LDL from oxidation. Atherosclerosis, 2001, 155: 229-235
36 Dandona P, Aljada A, Chaudhuri A, et al. Endothelial dysfunction, inflammation and diabetes. Rev Endocr Metab Disord, 2004, 5: 189-197
37 Matarese G, La Cava A, Sanna V, et al. Balancing susceptibility to infection and autoimmunity: a role for leptin? Trends Immunol, 2002, 23: 182-187
38 Miller GE, Freedland KE, Carney RM, et al. Pathways linking depression, adiposity, and inflammatory markers in healthy young adults. Brain Behav Immun, 2003, 17:276-285
39 Abdella NA, Mojiminiyi OA, Moussa MA, et al. Plasma leptin concentration in patients with Type 2 diabetes: relationship to cardiovascular disease risk factors and insulin resistance. Diabet Med, 2005, 22: 278-285
40 Trujillo ME, Scherer PE. Adiponectin - journey from an adipocyte secretory protein to biomarker of the metabolic syndrome. J Intern Med, 2005, 257: 167-175
41 Wallerstedt SM, Eriksson AL, Niklason A, et al. Serum leptin and myocardial infarction in hypertension. Blood Press, 2004, 13: 243-246
42 Pischon T, Girman CJ, Hotamisligil GS, et al. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA, 2004, 291:1730-1737
43 Newby AC, Zaltsman AB. Molecular mechanisms in intimal hyperplasia. J Pathol, 2000, 190: 300-309
44 Bochaton-Piallat ML, Gabbiani F, Redard M, et al. Apoptosis participates in cellularity regulation during rat aortic intimal thickening. Am J Pathol, 1995, 146: 1059-1064
45 Han DK, Haudenschild CC, Hong MK, et al. Evidence for apoptosis in human atherogenesis and in a rat vascular injury model. Am J Pathol, 1995, 147: 267- 277
46 Isner JM, Kearney M, Bortman S, et al. Apoptosis in human atherosclerosis and restenosis. Circulation, 1995, 91: 2703-2711
47 Henderson EL, Geng YJ, Sukhova GK, et al. Death of smooth muscle cells and expression of mediators of apoptosis by T lymphocytes in human abdominal aortic aneurysms. Circulation, 1999, 99: 96-104
48 Natarajan R, Gonzales N, Xu L, et al. Vascular smooth muscle cells exhibit increased growth in response to elevated glucose. Biochem Biophys Res Commun, 1992, 187: 552-560
49 Haikun Li, Sabine Te′ le′maque, Richard E, et al. High glucose inhibits apoptosis induced by serum deprivation in vascular smooth muscle cells via upregulation of Bcl-2 and Bcl-xl. Diabetes, 2005, 54: 540-545
50 Marx N, Schonbeck U, Lazar MA, et al. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res, 1998, 83: 1097-1103
51 Yki-Jarvinen H. Thiazolidinediones. N Engl J Med, 2004, 351: 1106-1118
52 Bailey CJ. Treating insulin resistance in type 2 diabetes with metformin and thiazolidinediones. Diabetes Obes Metab, 2005, 7: 675- 691
53 Verges B. Diabetic dyslipidaemia: insights for optimizing patient management. Curr Med Res Opin, 2005, 21: 29-40
54 van Wijk JP, de Koning EJ, Martens EP, et al. Thiazolidinediones and blood lipids in type 2 diabetes. Arterioscler Thromb Vasc Biol, 2003, 23: 1744-1749
55 Chiquette E, Ramirez G, DeFronzo R. A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors. Arch Intern Med, 2004, 164: 2097-2104
56 Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care, 2005, 28: 1547-1554
57 Berhanu P, Kipnes MS, Khan MA, et al. Effects of pioglitazone on lipid and lipoprotein profiles in patients with type 2 diabetes and dyslipidaemia after treatment conversion from rosiglitazone while continuing stable statin therapy. Diab Vasc Dis Res, 2006, 1: 39-44
58 Qayyum R, Schulman P. Cardiovascular effects of the thiazolidinediones. Diabetes Metab Res Rev, 2006, 22: 88-97
59 Natali A, Baldeweg S, Toschi E, et al. Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes. Diabetes Care, 2004, 27: 349-357
60 Raji A, Seely EW, Bekins SA, et al. Rosiglitazone improves insulin sensitivity and lowers blood pressure in hypertensive patients. Diabetes Care, 2003, 26: 72-78
61 Fullert S, Schneider F, Haak E, et al. Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebocontrolled study. J Clin Endocrinol Metab, 2002, 87: 5503-5506
62 Hetzel J, Balletshofer B, Rittig K, et al. Rapid effects of rosiglitazone treatment on endothelial function and inflammatory biomarkers. Arterioscler Thromb Vasc Biol, 2005, 25: 1804-1809
63 Erdmann E. Microalbuminuria as a marker of cardiovascular risk in patients with type 2 diabetes. Int J Cardiol, 2006, 107: 147-153
64 Haffner SM, Greenberg AS, Weston WM, et al. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation, 2002, 106:679-684
65 Bajaj M, Suraamornkul S, Piper P, et al. Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J Clin Endocrinol Metab, 2004, 89: 200-206
66 Li D, Chen K, Sinha N, et al. The effects of PPAR-gamma ligand pioglitazone on platelet aggregation and arterial thrombus formation. Cardiovasc Res, 2005, 65: 907-912
67 Calnek DS, Mazzella L, Roser S, et al. Peroxisome proliferator- activated receptor gamma ligands increase release of nitric oxide from endothelial cells. Arterioscler Thromb Vasc Biol, 2003, 23: 52-57
68 Zirlik A, Leugers A, Lohrmann J, et al. Direct attenuation of plasminogen activator inhibitor type-1 expression in human adipose tissue by thiazolidinediones. Thromb Haemost,2004, 91: 674-682
69 Derosa G, Cicero AF, Gaddi A, et al. A comparison of the effects of pioglitazone and rosiglitazone combined with glimepiride on prothrombotic state in type 2 diabetic patients with the metabolic syndrome. Diabetes Res Clin Pract, 2005, 69: 5-13
70 Sidhu JS, Cowan D, Tooze JA, et al. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reduces circulating platelet activity in patients without diabetes mellitus who have coronary artery disease. Am Heart J, 2004, 147: 1032-1037
71 Wakino S, Kintscher U, Kim S, et al. Peroxisome proliferator-activated receptor gamma ligands inhibit retinoblastoma phosphorylation and G13S transition in vascular smooth muscle cells. J Biol Chem, 2000, 275: 22435-22441
72 Bruemmer D, Yin F, Liu J, et al. Peroxisome proliferator-activated receptorγinhibits expression of minichromosome maintenance proteins in vascular smooth muscle cells. Mol Endocrinol, 2003, 17: 1005-1018
73 Bruemmer D, Yin F, Liu J, et al. Regulation of the growth arrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor γ in vascular smooth muscle cells. Circ Res, 2003, 93: 38-47
2 Wakino S, Kintscher U, Kim S, et al. Peroxisome proliferator-activated receptor gamma ligands inhibit retinoblastoma phosphorylation and G13S transition in vascular smooth muscle cells. J Biol Chem, 2000, 275: 22435-22441
3 Bruemmer D, Yin F, Liu J, et al. Peroxisome proliferator-activated receptor γ inhibits expression of minichromosome maintenance proteins in vascular smooth muscle cells. Mol Endocrinol, 2003, 17: 1005-1018
4 Bruemmer D, Yin F, Liu J, et al. Regulation of the growth arrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor γ in vascular smooth muscle cells. Circ Res, 2003, 93: 38-47
5 Sidhu JS, Kaposzta Z, Markus HS, et al. Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patients without diabetes mellitus. Arterioscler Thromb Vasc Biol, 2004, 24: 930-934
6 Tikellis C, Jandeleit-Dahm KA, Sheehy K, et al. Reduced plaque formation induced by rosiglitazone in anSTZ-diabetes mouse model of atherosclerosis is associated with downregulation of adhesion molecules. Elsevier Ireland Ltd, 2007, 10: 38-48
7 Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med, 1999, 340: 115-126
8 Wilson PWF, Cupples LA, Kannel WB. Is hyperglycemia associated with cardiovascular disease? The Framingham Study. Am Heart J, 1991, 121: 586-590
9 Li H, Te′ le′maque S, Miller RE, et al. High glucose inhibits apoptosis induced by serum deprivation in vascular smooth muscle cells via upregulation of Bcl-2 and Bcl-xl. Diabetes, 2005, 54: 540-545
10 Marx N, Schonbeck U, Lazar MA, et al. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res, 1998, 83: 1097-1103
11 Ricote M, Li AC, Willson TM, et al. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature, 1998, 391: 79-82
12 Ronald E, Goetze S, Xi XP, et al. Expression and function of PPAR γ in rat and human vascular smooth muscle cells. Circulation, 2000, 101: 1311-1318
13 Guan Y. Targeting peroxisome proliferators-activated receptors (PPARs) in kidney and urologic disease. Minerva Urol Nefrol, 2002, 54: 65-79
14 Guan Y, Zhang Y, Breyer MD. The role of PPARs in the transcriptional control of cellular processes. Drug News Perspect, 2002, 15: 147-154
15 Ricote M, Huang J, Fajas L, et al. Expression of the peroxisome proliferator-activated receptor (PPAR) in human atherosclerosis and regulation in macrophages by colony-stimulating factors and oxidized low-density lipoprotein. Proc Natl Acad Sci, 1998, 95(13): 7614-7619
16 de Dios ST, Hannan KM, Dilley RJ, et al. Troglitazone, but not rosiglitazone, inhibits Na/H exchange activity and proliferation of macrovascular endothelial cells. J Diabetes Complications, 2001, 15(3): 120-127
17 Masamune A, Kikuta K, Satoh M, et al. Ligands of peroxisome proliferator-activated receptor-gamma block activation of pancreatic stellate cells. J Biol Chem, 2002, 277(1): 141-147
18 Galli A, Crabb D, Price D, et al. Peroxisome proliferator-activated receptor gamma transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells. Hepatology, 2000, 31(1): 101-108
19 Hayon T, Dvilansky A, Shpilberg O, et al. Appraisal of the MTT-based assay as a useful tool for predicting drug chemosensitivity in leukemia. Leuk Lymphoma, 2003, 44(11): 1957-1962
20 MacCorkle RA, Tan TH. Mitogen-activated protein kinasesin cell-cycle control. Cell Biochem Biophys, 2005, 43(3): 451-461
21 Yamamoto M, Acevedo-Duncan M, Chalfant CE, et al. Acute glucose-induced downregulation of PKC-II accelerates cultured VSMC proliferation. Am J Physiol Cell Physiol, 2000, 279: 587-595
22 de Dios ST, Bruemmer D, Dilley TJ, et a1. Inhibitory acitivty of clinical htiazolidindeione peorxicsme porliferator acivating receptor-gamma ligands toward internal mammary artery, radial artery, and saphenous vein smooth muscle cell proliferation [J]. Ciroulation, 2003, 27: 2548-2550
1 Bochaton-Piallat ML, Gabbiani F, Redard M, et al. Apoptosis participates in cellularity regulation during rat aortic intimal thickening. Am J Pathol, 1995, 146: 1059-1064
2 Han DK, Haudenschild CC, Hong MK, et al. Evidence for apoptosis in human atherogenesis and in a rat vascular injury model. Am J Pathol, 1995, 147: 267-277
3 Pollman MJ, Hall JL, Mann MJ, et al. Inhibition of neointimal cell bcl-x expression induces apoptosis and regression of vascular disease. Nat Med, 1998, 4: 222-227
4 Haikun Li, Sabine Te′ le′maque, Richard E. Miller, et al. High glucose inhibits apoptosis induced by serum deprivation in vascular smooth muscle cells via upregulation of Bcl-2 and Bcl-xl. Diabetes, 2005, 54: 540-545
5 Bruemmer D, Yin F, Liu J, et al. Regulation of the growtharrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor γ in vascular smooth muscle cells. Circ Res, 2003, 93: 38-47
6 Law RE, Goetz S, Xi XP, et al. Expression and function of PPAR- γ in rat and human vascular smooth muscle cells. Circulation, 2000, 101(11): 1311-1318
7 Ricote M, Huang J, Fajas L, et al. Expression of the peroxisome proliferator-activated receptor (PPAR) in human atherosclerosis and regulation in macrophages by colony-stimulating factors and oxidized low-density lipoprotein. Proc Natl Acad Sci, 1998, 95(13): 7614-7619
8 Kockx MM, Knaapen MW. The role of apoptosis in vascular disease. J Pathol, 2000, 190: 267-280
9 Perlman H, Sata M, Krasinski K, et al. Adenovirusencoded hammerhead ribozyme to Bcl-2 inhibits neointimal hyperplasia and induces vascular smooth muscle cell apoptosis. Cardiovasc Res, 2000, 45: 570-578
10 Chinnaiyan AM, O’Rourke K, Lane BR, et al. Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death. Science, 1997, 275: 1122-1126
11 Decaudin D, Geley S, Hirsch T, et al. Bcl-2 and Bcl-XL antagonize the mitochondrial dysfunction preceding nuclear apoptosis induced by chemotherapeutic agents. Cancer Res, 1997, 57: 62- 67
12 Kharbanda S, Pandey P, Schofield L, et al. Role of Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis. Proc Natl Acad Sci USA, 1997, 94: 6939-6942
13 Leesnitzer LM, Parks DJ, Bledsoe RK, et al. Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry, 2002, 41: 6640-6650
1 Guan Y. Targeting Peroxisome proliferators-activated receptors (PPARs) in kidney and urologic disease. Minerva Urol Nefrol, 2002, 54:65-79
2 Guan Y, Zhang Y, Breyer MD. The role of PPARs in the transcriptional control of cellular processes. Drug News Perspect, 2002, 15: 147-154
3 Law RE, Goetze S, Xi XP, et al. Expression and function of PPARγ in rat and human vascular smooth muscle cells. Circulation, 2000, 101: 1311-1318
4 Ajjan R, Grant PJ. Coagulation and atherothrombotic disease. Atherosclerosis, 2006, 186:240-259
5 Madamanchi NR, Hakim ZS, Runge MS. Oxidative stress in atherogenesis and arterial thrombosis: the disconnect between cellular studies and clinical outcomes. J Thromb Haemost 2005, 3: 254-267
6 Newby AC. Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev, 2005, 85: 1-31
7 Rosenson RS, Koenig W. Utility of inflammatory markers inthe management of coronary artery disease. Am J Cardiol, 2003, 92: 10-18
8 Libby P, Ridker PM. Inflammation and atherosclerosis: role of C-reactive protein in risk assessment. Am J Med, 2004, 116(suppl 6A): 9-16
9 Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev, 1995, 75: 473-486
10 Reaven G. Syndrome X. Curr Treat Options Cardiovasc Med, 2001, 3: 323-332
11 Haffner SM, D'Agostino R Jr, Mykkanen L, et al. Insulin sensitivity in subjects with type 2 diabetes. Relationship to cardiovascular risk factors: the Insulin Resistance Atherosclerosis Study. Diabetes Care, 1999, 22:562-568
12 Henry RR. Insulin resistance: from predisposing factor to therapeutic target in type 2 diabetes. Clin Ther, 2003, 25: 47-63
13 Stolar MW, Chilton RJ. Type 2 diabetes, cardiovascular risk, and the link to insulin resistance. Clin Ther, 2003, 25: 4-31
14 Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomized placebo-controlled trial. Lancet, 2004, 364: 685-696
15 Betteridge DJ. Long-term risk reduction: who needs treatment? Diabetes Res Clin Pract, 2005, 68: 15-22
16 Ginsberg HN. Review: Efficacy and mechanisms of actionof statins in the treatment of diabetic dyslipidemia. J Clin Endocrinol Metab, 2006, 91: 383-392
17 JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart, 2005, 91(suppl 5): 1-52
18 Faergeman O. Hypertriglyceridemia and the fibrate trials. Curr Opin Lipidol, 2000, 11: 609-614
19 Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet, 2005, 366: 1849-1861
20 Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA, 1979, 241: 2035-2038
21 Kannel WB. Overview of hemostatic factors involved in atherosclerotic cardiovascular disease. Lipids, 2005, 40: 1215-122.
22 Stamler J, Vaccaro O, Neaton JD, et al.. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care, 1993, 16: 434-444
23 Adler AI, Stratton IM, Neil HA et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ, 2000, 321: 412-419
24 Mogensen CE, Chachati A, Christensen CK, et al.Microalbuminuria: an early marker of renal involvement in diabetes. Uremia Invest, 1985, 9: 85-95
25 Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA, 2001, 286: 421-426
26 Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, et al. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation, 2004, 110: 32-35
27 Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, et al. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia, 1989, 32: 219-226
28 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science, 1993, 259: 87-91
29 Dandona P, Weinstock R, Thusu K, et al. Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab, 1998, 83: 2907-2910
30 Yudkin JS, Stehouwer CD, Emeis JJ, et al. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol, 1999, 19: 972-978
31 Pickup JC, Mattock MB, Chusney GD, et al. NIDDM as a disease of the innate immune system: association ofacute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia, 1997, 40: 1286-1292
32 Blankenberg S, Rupprecht HJ, Bickel C, et al. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation, 2001, 104: 1336-1342
33 Esposito K, Nappo F, Giugliano F, et al. Cytokine milieu tends toward inflammation in type 2 diabetes. Diabetes Care, 2003, 26: 1647
34 Lee SW, Song KE, Shin DS, et al. Alterations in peripheral blood levels of TIMP-1, MMP-2, and MMP-9 in patients with type-2 diabetes. Diabetes Res Clin Pract, 2005, 69: 175-179
35 Boemi M, Leviev I, Sirolla C, et al. Serum paraoxonase is reduced in type 1 diabetic patients compared to nondiabetic, first degree relatives; influence on the ability of HDL to protect LDL from oxidation. Atherosclerosis, 2001, 155: 229-235
36 Dandona P, Aljada A, Chaudhuri A, et al. Endothelial dysfunction, inflammation and diabetes. Rev Endocr Metab Disord, 2004, 5: 189-197
37 Matarese G, La Cava A, Sanna V, et al. Balancing susceptibility to infection and autoimmunity: a role for leptin? Trends Immunol, 2002, 23: 182-187
38 Miller GE, Freedland KE, Carney RM, et al. Pathways linking depression, adiposity, and inflammatory markers in healthy young adults. Brain Behav Immun, 2003, 17:276-285
39 Abdella NA, Mojiminiyi OA, Moussa MA, et al. Plasma leptin concentration in patients with Type 2 diabetes: relationship to cardiovascular disease risk factors and insulin resistance. Diabet Med, 2005, 22: 278-285
40 Trujillo ME, Scherer PE. Adiponectin - journey from an adipocyte secretory protein to biomarker of the metabolic syndrome. J Intern Med, 2005, 257: 167-175
41 Wallerstedt SM, Eriksson AL, Niklason A, et al. Serum leptin and myocardial infarction in hypertension. Blood Press, 2004, 13: 243-246
42 Pischon T, Girman CJ, Hotamisligil GS, et al. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA, 2004, 291:1730-1737
43 Newby AC, Zaltsman AB. Molecular mechanisms in intimal hyperplasia. J Pathol, 2000, 190: 300-309
44 Bochaton-Piallat ML, Gabbiani F, Redard M, et al. Apoptosis participates in cellularity regulation during rat aortic intimal thickening. Am J Pathol, 1995, 146: 1059-1064
45 Han DK, Haudenschild CC, Hong MK, et al. Evidence for apoptosis in human atherogenesis and in a rat vascular injury model. Am J Pathol, 1995, 147: 267- 277
46 Isner JM, Kearney M, Bortman S, et al. Apoptosis in human atherosclerosis and restenosis. Circulation, 1995, 91: 2703-2711
47 Henderson EL, Geng YJ, Sukhova GK, et al. Death of smooth muscle cells and expression of mediators of apoptosis by T lymphocytes in human abdominal aortic aneurysms. Circulation, 1999, 99: 96-104
48 Natarajan R, Gonzales N, Xu L, et al. Vascular smooth muscle cells exhibit increased growth in response to elevated glucose. Biochem Biophys Res Commun, 1992, 187: 552-560
49 Haikun Li, Sabine Te′ le′maque, Richard E, et al. High glucose inhibits apoptosis induced by serum deprivation in vascular smooth muscle cells via upregulation of Bcl-2 and Bcl-xl. Diabetes, 2005, 54: 540-545
50 Marx N, Schonbeck U, Lazar MA, et al. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res, 1998, 83: 1097-1103
51 Yki-Jarvinen H. Thiazolidinediones. N Engl J Med, 2004, 351: 1106-1118
52 Bailey CJ. Treating insulin resistance in type 2 diabetes with metformin and thiazolidinediones. Diabetes Obes Metab, 2005, 7: 675- 691
53 Verges B. Diabetic dyslipidaemia: insights for optimizing patient management. Curr Med Res Opin, 2005, 21: 29-40
54 van Wijk JP, de Koning EJ, Martens EP, et al. Thiazolidinediones and blood lipids in type 2 diabetes. Arterioscler Thromb Vasc Biol, 2003, 23: 1744-1749
55 Chiquette E, Ramirez G, DeFronzo R. A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors. Arch Intern Med, 2004, 164: 2097-2104
56 Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care, 2005, 28: 1547-1554
57 Berhanu P, Kipnes MS, Khan MA, et al. Effects of pioglitazone on lipid and lipoprotein profiles in patients with type 2 diabetes and dyslipidaemia after treatment conversion from rosiglitazone while continuing stable statin therapy. Diab Vasc Dis Res, 2006, 1: 39-44
58 Qayyum R, Schulman P. Cardiovascular effects of the thiazolidinediones. Diabetes Metab Res Rev, 2006, 22: 88-97
59 Natali A, Baldeweg S, Toschi E, et al. Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes. Diabetes Care, 2004, 27: 349-357
60 Raji A, Seely EW, Bekins SA, et al. Rosiglitazone improves insulin sensitivity and lowers blood pressure in hypertensive patients. Diabetes Care, 2003, 26: 72-78
61 Fullert S, Schneider F, Haak E, et al. Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebocontrolled study. J Clin Endocrinol Metab, 2002, 87: 5503-5506
62 Hetzel J, Balletshofer B, Rittig K, et al. Rapid effects of rosiglitazone treatment on endothelial function and inflammatory biomarkers. Arterioscler Thromb Vasc Biol, 2005, 25: 1804-1809
63 Erdmann E. Microalbuminuria as a marker of cardiovascular risk in patients with type 2 diabetes. Int J Cardiol, 2006, 107: 147-153
64 Haffner SM, Greenberg AS, Weston WM, et al. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation, 2002, 106:679-684
65 Bajaj M, Suraamornkul S, Piper P, et al. Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J Clin Endocrinol Metab, 2004, 89: 200-206
66 Li D, Chen K, Sinha N, et al. The effects of PPAR-gamma ligand pioglitazone on platelet aggregation and arterial thrombus formation. Cardiovasc Res, 2005, 65: 907-912
67 Calnek DS, Mazzella L, Roser S, et al. Peroxisome proliferator- activated receptor gamma ligands increase release of nitric oxide from endothelial cells. Arterioscler Thromb Vasc Biol, 2003, 23: 52-57
68 Zirlik A, Leugers A, Lohrmann J, et al. Direct attenuation of plasminogen activator inhibitor type-1 expression in human adipose tissue by thiazolidinediones. Thromb Haemost,2004, 91: 674-682
69 Derosa G, Cicero AF, Gaddi A, et al. A comparison of the effects of pioglitazone and rosiglitazone combined with glimepiride on prothrombotic state in type 2 diabetic patients with the metabolic syndrome. Diabetes Res Clin Pract, 2005, 69: 5-13
70 Sidhu JS, Cowan D, Tooze JA, et al. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reduces circulating platelet activity in patients without diabetes mellitus who have coronary artery disease. Am Heart J, 2004, 147: 1032-1037
71 Wakino S, Kintscher U, Kim S, et al. Peroxisome proliferator-activated receptor gamma ligands inhibit retinoblastoma phosphorylation and G13S transition in vascular smooth muscle cells. J Biol Chem, 2000, 275: 22435-22441
72 Bruemmer D, Yin F, Liu J, et al. Peroxisome proliferator-activated receptorγinhibits expression of minichromosome maintenance proteins in vascular smooth muscle cells. Mol Endocrinol, 2003, 17: 1005-1018
73 Bruemmer D, Yin F, Liu J, et al. Regulation of the growth arrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor γ in vascular smooth muscle cells. Circ Res, 2003, 93: 38-47