罗格列酮对正常及2型糖尿病大鼠心肌缺血再灌注损伤的保护作用
|
摘要
近年来,糖尿病已经成为严重危害人类生活质量的重大疾病之一。研究证实,心绞痛,心肌梗死是糖尿病常见的心血管并发症,心肌梗死在糖尿病患者中的病死率较无糖尿病的患者高3倍～4倍。此外,心力衰竭和再梗死的发生率在合并糖尿病的心肌梗死患者中也明显增加。因此,糖尿病的治疗不仅要立足于降低血糖,更重要的是改善糖尿病造成的心肌代谢紊乱,降低心脑血管并发症。
罗格列酮(Rosiglitazone, RSG)是噻唑烷二酮类降糖药,具有提高机体对内源性胰岛素的敏感性,减轻2型糖尿病患者的胰岛素抵抗,纠正多种代谢紊乱和降低血糖作用,近年来在临床上广为应用。由于2型糖尿病患者本身是心血管疾病的高危人群,心血管疾病又是2型糖尿病的常见并发症,因此寻求具有改善糖尿病心血管并发症的降血糖药物并对其心血管保护机制进行研究具有重要意义。本课题拟观察罗格列酮对正常及糖尿病大鼠急性心肌缺血再灌注损伤心肌梗死面积,心律失常发生率和心肌病理学改变的影响,并深入探讨罗格列酮对2型糖尿病大鼠心肌缺血保护作用的机制。
本研究首先以结扎正常大鼠左冠状动脉前降支复制急性心肌缺血模型,观察缺血再灌注损伤后心肌梗死面积,心律失常发生次数和类型以及血压的变化,判断罗格列酮对正常大鼠心肌缺血的保护作用,结果发现罗格列酮组心肌梗死面积减小,心肌梗死面积与左心室面积百分率以及与危险区面积比值减少,心律失常评分降低,并且可以改善心肌病理组织学和心肌细胞超微结构损伤。说明罗格列酮对急性心肌损伤有良好的保护作用。
实验第二部分,我们继续观察了罗格列酮对糖尿病大鼠缺血再灌注损伤的保护作用。以高脂饮食联合小剂量多次腹腔注射链脲霉素(streptozotocin,STZ)建立大鼠2型糖尿病模型,结扎大鼠左冠状动脉前降支复制急性心肌缺血模型,同样,观察缺血再灌注损伤后心肌梗死面积,心律失常的发生及血压的变化。结果显示,罗格列酮给药组糖尿病大鼠心肌各项指标亦有明显改善。提示罗格列酮对糖尿病心肌病亦有显著的疗效。
糖尿病心肌病的发病机制目前仍然不是十分清楚,目前研究显示,能量代谢障碍是糖尿病心肌病发生的重要因素。心脏是机体对能量需求最高的器官之一。在糖尿病心肌细胞存在严重的糖脂代谢紊乱,由于胰岛素缺乏和(或)胰岛素抵抗使心肌细胞利用葡萄糖氧化来提供的能量减少,从利用葡萄糖和脂肪酸供能转变为几乎全部通过脂肪酸β-氧化提供能量。可以说,糖代谢异常是糖尿病心肌病发生的始动因素,脂质代谢障碍是糖尿病心肌病的促进因素。
过氧化物酶体增殖物激活型受体(peroxisome proliferator-activated receptor,PPAR),是由Issemann等于1990年发现的能被过氧化酶体增殖物激活的一类核转录因子。现证实其存在三种异构体,PPARα、PPAR-β/δ、PPARγ。其被配体激活后,通过结合目标基因启动子内反应元件,在转录水平调节相关基因表达。PPARγ对于调节全身组织代谢有极其重要的意义,尤其是脂肪酸及葡萄糖代谢。PPARγ参与脂质代谢、促进脂肪细胞分化的基因转录,增加脂肪酸转运蛋白和脂肪酸转运酶表达,刺激细胞对脂肪酸的摄入及向脂酞转化。
由于罗格列酮是PPARγ的特异性激动剂,因此,我们猜测罗格列酮对糖尿病心肌病的治疗作用可能是通过上调心肌组织中PPARγ的表达,PPARγ与配体结合后,通过调整下游基因表达,进而增强胰岛素的反应性及组织摄取糖,进而明显改善心肌能量代谢的作用。因此,我们检测了与心肌能量代谢相关的蛋白PPARγ,PPARγ辅助因子(PPARγcoactivator 1α, PGC-1α),解耦联蛋白2(UCP2),解耦联蛋白3(UCP3)表达的改变。结果显示,2型糖尿病大鼠心肌组织中PPARγ、PGC1、UCP2、UCP3蛋白表达增高。而与2型糖尿病大鼠相比,糖尿病伴缺血再灌注损伤组大鼠PPARγ、PGC1蛋白表达下调,UCP2蛋白急剧增高, UCP3蛋白表达亦明显上调;与缺血再灌注损伤组相比,罗格列酮组PPARγ、PGC1表达增高、UCP2及UCP3蛋白表达下调。实验结果表明,糖尿病心肌缺血大鼠PPARγ及PGC-1α表达下调,脂肪酸氧化障碍,心肌能量供给不足;同时PPARγ降低可上调心脏线粒体解耦联蛋白UCP2,UCP3过度表达,使物质氧化与磷酸化解耦联,从而阻止ATP合成,使能量以热能形式散失,表现为心肌能量耗竭。而罗格列酮组PPARγ及PGC-1α蛋白表达上调,UCP2及UCP3蛋白下调,提示罗格列酮可能是通过该途径改善心肌能量代谢,从而发挥其心肌保护作用。
In recent years, diabetes has become a seriously diseases endangered the human life. It is confirmed that angina pectoris and myocardial infarction are frequent cardiovascular complications in diabetic patients. The mortality of myocardial infarction in patients with diabetes was 3-4 times higher than those without it. In addition, heart failure and re-infarction are increased in the myocardial infarction patients combined with diabetes significantly. Therefore, the treatment of diabetes should not only be based on lowering blood glucose and, more importantly, to improve the diabetic metabolic disorder and reduce cardiovascular and cerebrovascular complications.
Rosiglitazone, a hypoglycemic agent of thiazolidinediones (TZDs), has attracted remarkable scientific interest on novel and potent improveing insulin- sensitizing agents, and to lighten insulin resistance, more over, to correct metabolic disturbance. Patients with type 2 diabetes are at a high risk for cardio- vascular disease,resulting in increased mortality rates. So there is an urgent need to develop a hypoglycemic agent with protective effects on the cardiova- scular system. In this topic, we will research the protective effects of Rosiglitazone on acute myocardial I/R injure in normal and Type 2 diabetic (T2DM) rats.
Rosiglitazone is a specific agonist of PPARγ. PPARγis an important factor for regulating body metabolism, in particular metabolism of fatty acid and glucose. It can promote adipocyte differentiation; increase the expression of fatty acid transport protein and fatty acid transporter enzyme. It also could stimulate fatty acids be intake and transformation, and enhance insulin-responsive and glucose uptake by adjusting the expression of downstream gene, thereby improve the energy metabolism of myocardial significantly. Therefore, we proposed to investigate the mechanism of rosiglitazone on the perspective of energy metabolism of myocardial.
Methods:
1.The effects of rosiglitazone on myocardial ischemia-reperfusion ( I/R) in normal rats: I/R injury rat model was induced via ligating left anterior descending branch of coronary artery for 30 min and reperfusing for 120 min; Rats were randomly divided into rosiglitazone, I/R and shame- operated group. Myocardial infarct size (IS) and the ratio of IS and area at risk (AAR) were determined, arrhythmias score was evaluated according to Lambeth conventions, and blood pressure (BP) was recorded 1 w after intragastric administration and I/R injury operation. The ultrastr- ucture of cadiocyte was observed by electron microscope.
2.The effects of rosiglitazone on myocardial ischemia-reperfusion (I-R) in T2DM rats: T2DM ratmodelwas established by high lipid diet combined multiple low dose strep tozocin (STZ); T2DM rats were randomly divided into rosiglitazone, I/R and shame-operated groups.
3. Myocardial protein was extracted in each group. The protein level of PPARγ、PGC1、UCP2 and UCP3 in cardiac muscle was measured using western blot. Actin,a conservative protein,was used as an interner control to adjust the concentration of each sample.
Results:
1. The effects of rosiglitazone on I/R in normal rats: Compared with IR group, rosiglitazone decreased the ration of IS/LV (29.3±4.9vs 37.6±3.2) and the rate of AAR /LV (76.1±9.6 vs 93.5±7.4), reduced scores of arrhythmias (2.6±0.4 vs 4.2±0.6) and ameliorated the restore of BP in reperfusion period (P < 0.05).
2. The effects of rosiglitazone on I/R in T2DM rats: Compared with IR group, rosiglitazone decreased the ration of IS/LV (30.3±3.6 vs 38.7±3.0) and the rate of AAR /LV (76.0±2.6 vs 93.2±3.0) , reduced scores of arrhythmias (2.6±0.4 vs 4.4±0.8) and ameliorated the restore of BP in reperfusion period (P < 0.05).
3. Compared with control group, PPARγ、PGC1、UCP2 and UCP3 are increased in the cardiac musculature. It is suggested that in diabetes, due to elevated blood sugar and abnormal glucose metabolism, there have been some changes on energy metabolism of myocardial and myocardial fatty acid oxidation may be enhance compensatory. However, the protein level of PPARγand PGC-1 decreased in DM-I-R group, with UCP2 sharply raised up. The UCP3 was also up-regulated in I-R group, compared with DM group. It shows that when myocardial ischemia was developed in diabetic rats, fatty acid dysoxidation was happen, combined with a serious shortage of oxygen supply, myocardial energy supply was insufficient; At the same time UCP2, UCP3 were over-expression, which made the oxidative phosphorylation uncoupling. Thereby it prevented ATP synthesis, and enhanced energy deficiency, manifested as myocardial energy depletion; And RSG can noteably swtch these changes, compared with I-R group.
Conclusions:
Rosiglitazone has the protective effects on acute myocardial I/R injure in normal and T2DM rats and it may be associated with the improvment of energy metabolism of cadiocyte.
罗格列酮(Rosiglitazone, RSG)是噻唑烷二酮类降糖药,具有提高机体对内源性胰岛素的敏感性,减轻2型糖尿病患者的胰岛素抵抗,纠正多种代谢紊乱和降低血糖作用,近年来在临床上广为应用。由于2型糖尿病患者本身是心血管疾病的高危人群,心血管疾病又是2型糖尿病的常见并发症,因此寻求具有改善糖尿病心血管并发症的降血糖药物并对其心血管保护机制进行研究具有重要意义。本课题拟观察罗格列酮对正常及糖尿病大鼠急性心肌缺血再灌注损伤心肌梗死面积,心律失常发生率和心肌病理学改变的影响,并深入探讨罗格列酮对2型糖尿病大鼠心肌缺血保护作用的机制。
本研究首先以结扎正常大鼠左冠状动脉前降支复制急性心肌缺血模型,观察缺血再灌注损伤后心肌梗死面积,心律失常发生次数和类型以及血压的变化,判断罗格列酮对正常大鼠心肌缺血的保护作用,结果发现罗格列酮组心肌梗死面积减小,心肌梗死面积与左心室面积百分率以及与危险区面积比值减少,心律失常评分降低,并且可以改善心肌病理组织学和心肌细胞超微结构损伤。说明罗格列酮对急性心肌损伤有良好的保护作用。
实验第二部分,我们继续观察了罗格列酮对糖尿病大鼠缺血再灌注损伤的保护作用。以高脂饮食联合小剂量多次腹腔注射链脲霉素(streptozotocin,STZ)建立大鼠2型糖尿病模型,结扎大鼠左冠状动脉前降支复制急性心肌缺血模型,同样,观察缺血再灌注损伤后心肌梗死面积,心律失常的发生及血压的变化。结果显示,罗格列酮给药组糖尿病大鼠心肌各项指标亦有明显改善。提示罗格列酮对糖尿病心肌病亦有显著的疗效。
糖尿病心肌病的发病机制目前仍然不是十分清楚,目前研究显示,能量代谢障碍是糖尿病心肌病发生的重要因素。心脏是机体对能量需求最高的器官之一。在糖尿病心肌细胞存在严重的糖脂代谢紊乱,由于胰岛素缺乏和(或)胰岛素抵抗使心肌细胞利用葡萄糖氧化来提供的能量减少,从利用葡萄糖和脂肪酸供能转变为几乎全部通过脂肪酸β-氧化提供能量。可以说,糖代谢异常是糖尿病心肌病发生的始动因素,脂质代谢障碍是糖尿病心肌病的促进因素。
过氧化物酶体增殖物激活型受体(peroxisome proliferator-activated receptor,PPAR),是由Issemann等于1990年发现的能被过氧化酶体增殖物激活的一类核转录因子。现证实其存在三种异构体,PPARα、PPAR-β/δ、PPARγ。其被配体激活后,通过结合目标基因启动子内反应元件,在转录水平调节相关基因表达。PPARγ对于调节全身组织代谢有极其重要的意义,尤其是脂肪酸及葡萄糖代谢。PPARγ参与脂质代谢、促进脂肪细胞分化的基因转录,增加脂肪酸转运蛋白和脂肪酸转运酶表达,刺激细胞对脂肪酸的摄入及向脂酞转化。
由于罗格列酮是PPARγ的特异性激动剂,因此,我们猜测罗格列酮对糖尿病心肌病的治疗作用可能是通过上调心肌组织中PPARγ的表达,PPARγ与配体结合后,通过调整下游基因表达,进而增强胰岛素的反应性及组织摄取糖,进而明显改善心肌能量代谢的作用。因此,我们检测了与心肌能量代谢相关的蛋白PPARγ,PPARγ辅助因子(PPARγcoactivator 1α, PGC-1α),解耦联蛋白2(UCP2),解耦联蛋白3(UCP3)表达的改变。结果显示,2型糖尿病大鼠心肌组织中PPARγ、PGC1、UCP2、UCP3蛋白表达增高。而与2型糖尿病大鼠相比,糖尿病伴缺血再灌注损伤组大鼠PPARγ、PGC1蛋白表达下调,UCP2蛋白急剧增高, UCP3蛋白表达亦明显上调;与缺血再灌注损伤组相比,罗格列酮组PPARγ、PGC1表达增高、UCP2及UCP3蛋白表达下调。实验结果表明,糖尿病心肌缺血大鼠PPARγ及PGC-1α表达下调,脂肪酸氧化障碍,心肌能量供给不足;同时PPARγ降低可上调心脏线粒体解耦联蛋白UCP2,UCP3过度表达,使物质氧化与磷酸化解耦联,从而阻止ATP合成,使能量以热能形式散失,表现为心肌能量耗竭。而罗格列酮组PPARγ及PGC-1α蛋白表达上调,UCP2及UCP3蛋白下调,提示罗格列酮可能是通过该途径改善心肌能量代谢,从而发挥其心肌保护作用。
In recent years, diabetes has become a seriously diseases endangered the human life. It is confirmed that angina pectoris and myocardial infarction are frequent cardiovascular complications in diabetic patients. The mortality of myocardial infarction in patients with diabetes was 3-4 times higher than those without it. In addition, heart failure and re-infarction are increased in the myocardial infarction patients combined with diabetes significantly. Therefore, the treatment of diabetes should not only be based on lowering blood glucose and, more importantly, to improve the diabetic metabolic disorder and reduce cardiovascular and cerebrovascular complications.
Rosiglitazone, a hypoglycemic agent of thiazolidinediones (TZDs), has attracted remarkable scientific interest on novel and potent improveing insulin- sensitizing agents, and to lighten insulin resistance, more over, to correct metabolic disturbance. Patients with type 2 diabetes are at a high risk for cardio- vascular disease,resulting in increased mortality rates. So there is an urgent need to develop a hypoglycemic agent with protective effects on the cardiova- scular system. In this topic, we will research the protective effects of Rosiglitazone on acute myocardial I/R injure in normal and Type 2 diabetic (T2DM) rats.
Rosiglitazone is a specific agonist of PPARγ. PPARγis an important factor for regulating body metabolism, in particular metabolism of fatty acid and glucose. It can promote adipocyte differentiation; increase the expression of fatty acid transport protein and fatty acid transporter enzyme. It also could stimulate fatty acids be intake and transformation, and enhance insulin-responsive and glucose uptake by adjusting the expression of downstream gene, thereby improve the energy metabolism of myocardial significantly. Therefore, we proposed to investigate the mechanism of rosiglitazone on the perspective of energy metabolism of myocardial.
Methods:
1.The effects of rosiglitazone on myocardial ischemia-reperfusion ( I/R) in normal rats: I/R injury rat model was induced via ligating left anterior descending branch of coronary artery for 30 min and reperfusing for 120 min; Rats were randomly divided into rosiglitazone, I/R and shame- operated group. Myocardial infarct size (IS) and the ratio of IS and area at risk (AAR) were determined, arrhythmias score was evaluated according to Lambeth conventions, and blood pressure (BP) was recorded 1 w after intragastric administration and I/R injury operation. The ultrastr- ucture of cadiocyte was observed by electron microscope.
2.The effects of rosiglitazone on myocardial ischemia-reperfusion (I-R) in T2DM rats: T2DM ratmodelwas established by high lipid diet combined multiple low dose strep tozocin (STZ); T2DM rats were randomly divided into rosiglitazone, I/R and shame-operated groups.
3. Myocardial protein was extracted in each group. The protein level of PPARγ、PGC1、UCP2 and UCP3 in cardiac muscle was measured using western blot. Actin,a conservative protein,was used as an interner control to adjust the concentration of each sample.
Results:
1. The effects of rosiglitazone on I/R in normal rats: Compared with IR group, rosiglitazone decreased the ration of IS/LV (29.3±4.9vs 37.6±3.2) and the rate of AAR /LV (76.1±9.6 vs 93.5±7.4), reduced scores of arrhythmias (2.6±0.4 vs 4.2±0.6) and ameliorated the restore of BP in reperfusion period (P < 0.05).
2. The effects of rosiglitazone on I/R in T2DM rats: Compared with IR group, rosiglitazone decreased the ration of IS/LV (30.3±3.6 vs 38.7±3.0) and the rate of AAR /LV (76.0±2.6 vs 93.2±3.0) , reduced scores of arrhythmias (2.6±0.4 vs 4.4±0.8) and ameliorated the restore of BP in reperfusion period (P < 0.05).
3. Compared with control group, PPARγ、PGC1、UCP2 and UCP3 are increased in the cardiac musculature. It is suggested that in diabetes, due to elevated blood sugar and abnormal glucose metabolism, there have been some changes on energy metabolism of myocardial and myocardial fatty acid oxidation may be enhance compensatory. However, the protein level of PPARγand PGC-1 decreased in DM-I-R group, with UCP2 sharply raised up. The UCP3 was also up-regulated in I-R group, compared with DM group. It shows that when myocardial ischemia was developed in diabetic rats, fatty acid dysoxidation was happen, combined with a serious shortage of oxygen supply, myocardial energy supply was insufficient; At the same time UCP2, UCP3 were over-expression, which made the oxidative phosphorylation uncoupling. Thereby it prevented ATP synthesis, and enhanced energy deficiency, manifested as myocardial energy depletion; And RSG can noteably swtch these changes, compared with I-R group.
Conclusions:
Rosiglitazone has the protective effects on acute myocardial I/R injure in normal and T2DM rats and it may be associated with the improvment of energy metabolism of cadiocyte.
引文
[1]Rullber S,Dulgush J, Yuceogl YZ, et al. New type of cardiomyopathy associated with diabetic Glomeruloselerosis[ J ]. Am J Cardiol, 1972, 30: 595
[2]Hamlby R I, Zoneraich S, Sheman L. Diabetic cardiomyopathy[J]. JAMA, 1974, 23, 229 (13) : 1749-1754.
[3]LIEDTKE A J,DEMAISON L, EGGLESTON A M, et al. Changes in substrate metabolism and effects of excess fatty acids in reperfused myocardium [J]. Circ Res, 1988, 62 (3) : 535-542.
[4]Ren J ,Davidoff AJ . Diabetes rapidly induces contractile dysfunctions in isolated ventricular myocytes[J ] . AmJ Physiol Heart Circ Physiol, 1997 ,272(1): 148-158.
[5]Kolb H, Kolb Bachofen V. Nitric oxide: a pathogenetic factor in autoimmunity[J]. Immunol Today, 1992, 13 (5) : 156-160.
[6]Galderisi M. Diastolic dysfunction and diabetic cardiomyopathy: evaluation by Doppler echocardiography [J ] . J Am Coll Cardiol ,2006 , 17 ; 48 : 1548-1551.
[7]Ramirez LC , Arauz Pacheco C , Lackner C , et al.Lipoprotein ( a ) levels in diabetes mellitus : relationship to metabolic control. Ann Interned 1992 ; 117 : 42 - 47.
[8]Kennedy AL , Lyons TJ . Glycation , oxidation ,and lipoxidation in the development of diabetic complications.Metabolism 1997; 46 : 14-21.
[9]Sambandam N,Abrahani MA, Craig S,et al.Am J Physiol Heart Circ Physiol,2000;278(6):H1874-H1882.
[10]Golfman LS ,Wilson CR ,Sharma S , et al . Activation of PPARgamma enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF rats [J]. Am J Physiol Endocrinol Metab, 2005 ,289(2) :E328-E336.
[11]Kennedy AL ,Lyons TJ . Glycation ,oxidation ,and lipoxidation in thedevelopment of diabetic complications [J ].Metabolism,1997 ,46 (1) : 14-21.
[12]Go lfman L , D ixon IM , Takeda N, et al. Cardiac sarco lemmal Na~+-Ca~(2+) exchange and Na~+-K~+ ATPase activities and gene expression in alloxan-induced diabetes in rats. Mol Cell Biochem,1998, 188 (1-2) : 91-101.
[13]蒋彬,周希平,蒋文平等.钠-钙交换与慢性心力衰竭[J].心血管病学进展, 2002, 23:371-374.
[14]Fiordaliso F, LiB, LatiniR, et al. Myocyte death in strep tozo tocin-induced diabetes in rats in angio tensinⅡ-dependent [J ]. Lab Invest, 2000, 80 (4) : 513-527.
[15]边延涛,王国宏,袁申元等.氯沙坦对实验性糖尿病大鼠心肌的保护作用.中华心血管病杂志2000, 28(4) : 293-296.
[16]Feng Q ,Lambert ML ,Callow ID ,et al . Venous neuropeptide Y receptor responsiveness in patients with chronic heart failure [J] . Clin Pharmacol Ther ,2000 ,67 (3) :292-298.
[17]Millar BC ,Piper HM,McDermott BJ . The antiadrenergic effect of neuropeptide Yon the ventricular cardiomyocyte[J] . Naunyn Schmiedebergs Arch. Pharmacol ,1988 ,338 (4) :426-429.
[18]Giles TD,Quyang J. Changes in p rotein in kinase C in early cardiomyopathy and in gracilis muscle in the BB /Wordiabetic rat[J]. Am - J - Physial, 1998, 274 (1p t2) : H295 .
[19]Giles TD,Quyang J, Kerut EK, et al. Changes in p rotein in kinase C in early cardiomyopathy and in gracilis muscle in the BB /Wordiabetic rat[J]. Am J Physial, 1998, 273: 295-307.
[20]CHEN S, EVANS T,MUKHERJEE K, et al. Diabetes-induced myoc- ardial structural changes: role of endothelin-1 and its receptors[J]. J Mol Cell Cardiol, 2000, 32 (9) : 1621-1629.
[21]朱莉,徐道亮,朱妍,等.糖尿病心肌组织中NOS的改变与糖尿病心肌病关系探讨[J].江苏医药杂志,2001 ,27 (10) :739.
[22]BOJESTIGM,NYSTROM F H,ARNQV IST H J , et al. The renin- angiotensin-aldosterone system is suppressed in adults with type 1 diabetes [J]. J Renin Angiotensin Aldosterone Syst,2000, 1 (4) : 353-356.
[23]Norby FL,Wold LE,Duaan J,et al. Am J Physiol Endocrinol Metab, 2002,283(4):E658-E666.
[24]Cai L,Kang YJ.Cardiovasc Toxicol,2001,1(3):181～193.
[25]Yorek MA. The role of oxidative stress in diabetic vascular and neural disease [J]. Free Radic Res ,2003 ,37 (5) :471-480.
[26]KONDO K,MATSUBARA T,NAKAMURA J, et al. Characteristic patterns of circadian variation in plasma catecholamine levels, blood pressure and heart rate variability in type 2 diabetic patients [J]. Diabet Med, 2002, 19 (5) : 359-365.
[27]丛丽,俞茂华,李益明,等.心肌胶原代谢变化在糖尿病心肌病变发生中作用的实验研究[J].中国临床康复, 2004 , 8 ( 9) :1655.
[28]Nishikawa N , Yamamoto K, Sakata Y, et al . Differential activation of matrix metalloproteinases in heart failure with and without ventricular dilatation[J]. Cardiovasc Res ,2003 ,57 (3):766-774.
[29]Zhang F, Li G, et al. Zhonghua Nei Ke Za Zhi. 2002,41(8):530-533
[30]Finck BN,Han X, Courtois M,et al.Proc Natl Acad Sci USA.2003, 100(3): 1226-1231 .
[31]Finck BN,Lehman JJ,Leone JC,et al.J Cha Invest.2002,109(1):121-130 .
[32]Puigserver P, Rhee J, Donovan J, et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 2003, 423: 550-5.
[33]Kawakami Y, Tsuda M, Takahashi S, et al. Transcriptional coactivator PGC-1alpha regulates chondrogenesis via association with Sox9. Proc Natl Acad Sci USA 2005, 102:2414-9.
[34]Kamei Y, Ohizumi H, Fujitani Y, et al. PPARgamma coactivator1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc Natl Acad Sci USA 2003,100:12378-83.
[35]Lin J, Tarr PT, Yang R, et al. PGC-1beta in the regulation of hepatic glucose and energy metabolism. J Biol Chem 2003, 278:30843-8.
[36]Spiegelman BM, Heinrich R. Biological control through regulated transcriptional coactivators. Cell. 2004, 119:157-67.
[37]Lin J, Yang R, Tarr PT, et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. Cell 2005, 120:261-73.
[38]Schreiber SN, Emter R, Hock MB, et al. The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)- induced mitochondrial biogenesis. Proc Natl Acad Sci U S A 2004, 101:6472-7.
[39]Wallberg AE, Yamamura S, Malik S, Spiegelman BM, Roeder RG. Coordination of p300-mediated chromatin remodeling and TRAP/mediator function through coactivator PGC-1alpha. Mol Cell 2003, 12:1137-49.
[40]Monsalve M, Wu Z, Adelmant G, Puigserver P, Fan M, Spiegelman BM. Direct coupling of transcription and mRNA processing through the thermogenic coactivator PGC-1. Mol Cell 2000, 6:307-16.
[41]Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP. Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest 2000, 106:847-56.
[42]Arany Z, He H, Lin J, et al. Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab 2005, 1:259-71.
[43]Huss JM, Kopp RP, Kelly DP. Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha. J Biol Chem 2002, 277:40265-74.
[44]Finck BN, Lehman JJ, Leone TC, et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 2002, 109:121-30.
[45]Sano M, Wang SC, Shirai M, et al. Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure. Embo J 2004, 23:3559-69.
[46]金朝阳,邹大进.游离脂肪酸致胰岛素抵抗的机制[J]. 1999. ed. 247.
[47]文重远,陈小琳.双重胰岛抵抗对糖尿病大鼠心肌能量代谢及心功能的影响[J]. 2005, 200.
[48]D D, DJ R. Emerging therapies targeting hing-density lipoprotein metabolism and revers cholesterol transport[J]. 2006. , 1140-50.
[49]李莲静,陈晓虎.罗格列酮对原发性高血压伴2型糖尿病患者血压的影响[J]。2007. 667-8.
[50]SK J, SY Y. Alpha-MSH decrease apoptosis in ischemic acute renal failure in rats:possible mechanism of this beneficial effect[J]. 2001, 1583.
[51]郭晓风,李秀丽.罗格列酮的药理学研究概况[J]. 2006, 138-9.
[52]TD W, WJ C. Effects of rosiglitazone on endothelial function, C-reactive protein, and components of the metabolic syndrome in nondiabetic patients with the metabolic syndrome[J]. 2004.
[53]M S, J W. Treatment with rosiglitazone reduces hyperinsulinemia and improves arterial elasticity in patients with type 2 diabetes mellitus[J]. 2003.
[54]DS C, L M. Peroxisome proliferator-activated receptorγligands increase release of nitric oxide from endothelial cells. 2003. 52-57.
[55]Y F, H I. Thiazolidinediones, peroxisome proliferator-activated receptor gamma agonists, regulate endothelial cell growth and secretion of vasoactive peptides[J]. 2001, 113-9.
[56]QN D, ME1 M. Structure,endothelial function, cell growth, and inflammation in blood vessels of angiotensinⅡ-infused rats: role of peroxisome proliferator- activated receptor-γ[J]. 2002. 2296-302.
[57]M I. RM T. Effect of peroxisome proliferator-activated receptor-αand -γactivators on vascular remodeling in endothelin-dependent hypertension[J]. 2003. 45-51.
[58]陆晓骅,鲍思蔚.罗格列酮对冠心病合并2型糖尿病患者IL-6、TNF-α的影响[J]. 2007. 891-2.
[59]Myazaki Y, Glass L. Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in TypeⅡdiabetic patients[J]. 2001, 2-10.
[60]AB, RS H, The effect of rosiglitazone on insulin sensitivity,lipolysis,and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes[J]. 2002, 797.
[61]邵建政.罗格列酮对2型糖尿病血浆脂代谢和C反应蛋白的影响[J].交通医学,2007.
[62]C J, T TA.PPARr agonists inhibit production of monocyte inflammatory cytokines[J]. 1998. 82-6.
[63]O G, S J.Atorvastatin activates PPAR-gamma and attenuates the inflam- matory response in human monocytes[J]. 2002. 58-62.
[64]Y T,Y K. Vascular inflammation is negatively autoregulated by interaction between CCAAT/enhancer-binding protein-delta and peroxisome proliferator- activated receptor-gamma[J].Circ Res, 2002, 91(5):427-433. 2002,427-33.
[65]JI B. The relation of markers of inflammation to the development of glucose disorders in the elderly[J]. 2001. ABRAJA L, 2384-9.
[66]丁健,陈海燕.罗格列酮对兔动脉粥样硬化心血管系统超微结构的影响[J]. 2008. 342-4.
[67]王莉,刘素筠.罗格列酮对STZ诱导的糖尿病大鼠大血管超微结构的影响[J]. 2007, 1074-7.
[68]E LR,S G. Expression and function of PPAR in rat and human vascular smooth muscle cells[J]. 2000. 1311-8.
[69]I I, K S.Expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary cultures of human vascular endothelial cells[J]. 1998. 370-4.
[70]范彩逢,李恩.罗格列酮对急性心肌梗死大鼠心肌细胞凋亡及其基因表达的影响[J]. 2008,183-5.
[71]陈海燕,李杰.罗格列酮对SHR大鼠降压作用和靶器官保护机制研究[J].中国老年学杂志. 2007,1970-3.
[72]汪涛,秦志平.罗格列酮对大鼠心肌梗死后心肌肥厚标志基因BNP影响[J]. 2007. 6-8.
[73]Franconi F, Seghieri G, Canu S, Straface E, Campesi I, Malorni W. Are the available experimental models of type 2 diabetes appropriate for a gender perspective[J]. Pharmacol Res 2008;57:6-18.
[74]Sahin K, Onderci M, Tuzcu M, et al. Effect of chromium on carbohydrate and lipid metabolism in a rat model of type 2 diabetes mellitus: the fat-fed, streptozotocin-treated rat[J]. Metabolism. 2007;56:1233-40.
[75]Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening[J]. Pharmacol Res 2005;52:313-20.
[76]Reed MJ, Meszaros K, Entes LJ, et al. A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat[J]. Metabolism 2000;49:1390-4.
[77]Zhao S, Chu Y, Zhang C, et al. Diet-induced central obesity and insulin resistance in rabbits[J]. J Anim Physiol Anim Nutr (Berl) 2008;92:105-11.
[78]Flanagan AM, Brown JL, Santiago CA, Aad PY, Spicer LJ, Spicer MT. High-fat diets promote insulin resistance through cytokine gene expression in growing female rats[J]. J Nutr Biochem 2008;19:505-13.
[79]Tanaka S, Hayashi T, Toyoda T, et al. High-fat diet impairs the effects of a single bout of endurance exercise on glucose transport and insulin sensitivity in rat skeletal muscle[J]. Metabolism 2007;56:1719-28.
[80]Sotnikova R, Skalska S, Okruhlicova L, et al. Changes in the function and ultrastructure of vessels in the rat model of multiple low dose streptozotocin-induced diabetes[J]. Gen Physiol Biophys 2006;25:289-302.
[81]Kim E, Sohn S, Lee M, Jung J, Kineman RD, Park S. Differential responses of the growth hormone axis in two rat models of streptozotocin- induced insulinopenic diabetes[J]. J Endocrinol 2006;188:263-70.
[82]Howarth FC, Qureshi A, Shahin A, Lukic ML. Effects of single high-dose and multiple low-dose streptozotocin on contraction and intracellular Ca2+ in ventricular myocytes from diabetes resistant and susceptible rats[J]. Mol Cell Biochem 2005;269:103-8.
[83]Kannan Y, Tokunaga M, Moriyama M, Kinoshita H, Nakamura Y. Beneficial effects of troglitazone on neutrophil dysfunction in multiple low-dose streptozotocin-induced diabetic mice[J]. Clin Exp Immunol 2004;137:263-71.
[84]Friesen NT, Buchau AS, Schott-Ohly P, Lgssiar A, Gleichmann H. Generation of hydrogen peroxide and failure of antioxidative responses in pancreatic islets of male C57BL/6 mice are associated with diabetes induced by multiple low doses of streptozotocin[J]. Diabetologia 2004;47:676-85.
[85]Jr Wright JR, Lacy PE. Synergistic effects of adjuvants, endotoxin, and fasting on induction of diabetes with multiple low doses of streptozocin in rats[J]. Diabetes 1988;37:112-8.
[86]Yu De-min ,Yu Pei. The consideration about the cardiovascular safety of rosiglitazone[J]. Journal of china prescribed drug, 2007, 7(64):51-53.
[87]Steven E, Nissen, Kathy Wolski. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes[J]. N Engl J Med, 2007,356(24):2457-2471.
[88]Nassirah Khandoudi, Philippe Delerive, Isabelle Berrebi Bertrand, et al. Rosiglitazone, a Peroxisome Proliferator Activated Receptor-γ, Inhibits the Jun NH2-Terminal Kinase/Activating Protein 1 Pathway and Protects the Heart From Ischemia/Reperfusion Injury[J]. Diabetes, 2002, 51: 1507-1514.
[89]Behzad Molavi, Jiawei Chen, and J. L. Mehta. Cardioprotective effects of rosiglitazone are associated with selective overexpression of type 2 angiotensin receptors and inhibition of p42/44 MAPK[J]. Am J Physiol Heart Circ Physiol, 2006, 291: H687-H693.
[90]Douglas G. Johns, Zhaohui Ao, Marianne Eybye, et al. Rosiglitazone Protects against Ischemia/Reperfusion-Induced Leukocyte Adhesion in the Zucker Diabetic Fatty Rat[J]. JPET 2005, 315(3): 1020-1027.
[91]Ni-Huiping Son, Tae-Sik Park, Haruyo Yamashita, etal. Cardiomyocyte expression of PPARγleads to cardiac dysfunction in mice[J]. The Journal of Clinical Investigation, 2007, 17(10):2791-2801
[92]Liang CHEN, Sai Ma, Long-xiao Wei, et al. Cardioprotective and antiarrhythmic effect of U50,488H in ischemia/reperfusion rat heart[J]. Heart vessel, 2007,22:335-344.
[93]Gao F,Yue TL, Shi DW, et al. p38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation[J] . Cadiovasc Res, 2002,53,414-422.
[94]Walker MJ, Curtis MJ, Hearse DJ, et al. The Lambeth Conventions guidelines for the study of arrhythmias in ischaemia infarction, and reperfusion[J]. Cardiovasc Res,1988,22:447-455.
[95]Joosen AM, Bakker AH, Kersten S, etal. The PPARgamma ligand rosiglitazone influences triacylglycerol metabolism in non-obese males, without increasing the transcriptional activity of PPARgamma in the subcutaneous adipose tissue[J]. Br J Nutr, 2008, 99(3):487-493.
[2]Hamlby R I, Zoneraich S, Sheman L. Diabetic cardiomyopathy[J]. JAMA, 1974, 23, 229 (13) : 1749-1754.
[3]LIEDTKE A J,DEMAISON L, EGGLESTON A M, et al. Changes in substrate metabolism and effects of excess fatty acids in reperfused myocardium [J]. Circ Res, 1988, 62 (3) : 535-542.
[4]Ren J ,Davidoff AJ . Diabetes rapidly induces contractile dysfunctions in isolated ventricular myocytes[J ] . AmJ Physiol Heart Circ Physiol, 1997 ,272(1): 148-158.
[5]Kolb H, Kolb Bachofen V. Nitric oxide: a pathogenetic factor in autoimmunity[J]. Immunol Today, 1992, 13 (5) : 156-160.
[6]Galderisi M. Diastolic dysfunction and diabetic cardiomyopathy: evaluation by Doppler echocardiography [J ] . J Am Coll Cardiol ,2006 , 17 ; 48 : 1548-1551.
[7]Ramirez LC , Arauz Pacheco C , Lackner C , et al.Lipoprotein ( a ) levels in diabetes mellitus : relationship to metabolic control. Ann Interned 1992 ; 117 : 42 - 47.
[8]Kennedy AL , Lyons TJ . Glycation , oxidation ,and lipoxidation in the development of diabetic complications.Metabolism 1997; 46 : 14-21.
[9]Sambandam N,Abrahani MA, Craig S,et al.Am J Physiol Heart Circ Physiol,2000;278(6):H1874-H1882.
[10]Golfman LS ,Wilson CR ,Sharma S , et al . Activation of PPARgamma enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF rats [J]. Am J Physiol Endocrinol Metab, 2005 ,289(2) :E328-E336.
[11]Kennedy AL ,Lyons TJ . Glycation ,oxidation ,and lipoxidation in thedevelopment of diabetic complications [J ].Metabolism,1997 ,46 (1) : 14-21.
[12]Go lfman L , D ixon IM , Takeda N, et al. Cardiac sarco lemmal Na~+-Ca~(2+) exchange and Na~+-K~+ ATPase activities and gene expression in alloxan-induced diabetes in rats. Mol Cell Biochem,1998, 188 (1-2) : 91-101.
[13]蒋彬,周希平,蒋文平等.钠-钙交换与慢性心力衰竭[J].心血管病学进展, 2002, 23:371-374.
[14]Fiordaliso F, LiB, LatiniR, et al. Myocyte death in strep tozo tocin-induced diabetes in rats in angio tensinⅡ-dependent [J ]. Lab Invest, 2000, 80 (4) : 513-527.
[15]边延涛,王国宏,袁申元等.氯沙坦对实验性糖尿病大鼠心肌的保护作用.中华心血管病杂志2000, 28(4) : 293-296.
[16]Feng Q ,Lambert ML ,Callow ID ,et al . Venous neuropeptide Y receptor responsiveness in patients with chronic heart failure [J] . Clin Pharmacol Ther ,2000 ,67 (3) :292-298.
[17]Millar BC ,Piper HM,McDermott BJ . The antiadrenergic effect of neuropeptide Yon the ventricular cardiomyocyte[J] . Naunyn Schmiedebergs Arch. Pharmacol ,1988 ,338 (4) :426-429.
[18]Giles TD,Quyang J. Changes in p rotein in kinase C in early cardiomyopathy and in gracilis muscle in the BB /Wordiabetic rat[J]. Am - J - Physial, 1998, 274 (1p t2) : H295 .
[19]Giles TD,Quyang J, Kerut EK, et al. Changes in p rotein in kinase C in early cardiomyopathy and in gracilis muscle in the BB /Wordiabetic rat[J]. Am J Physial, 1998, 273: 295-307.
[20]CHEN S, EVANS T,MUKHERJEE K, et al. Diabetes-induced myoc- ardial structural changes: role of endothelin-1 and its receptors[J]. J Mol Cell Cardiol, 2000, 32 (9) : 1621-1629.
[21]朱莉,徐道亮,朱妍,等.糖尿病心肌组织中NOS的改变与糖尿病心肌病关系探讨[J].江苏医药杂志,2001 ,27 (10) :739.
[22]BOJESTIGM,NYSTROM F H,ARNQV IST H J , et al. The renin- angiotensin-aldosterone system is suppressed in adults with type 1 diabetes [J]. J Renin Angiotensin Aldosterone Syst,2000, 1 (4) : 353-356.
[23]Norby FL,Wold LE,Duaan J,et al. Am J Physiol Endocrinol Metab, 2002,283(4):E658-E666.
[24]Cai L,Kang YJ.Cardiovasc Toxicol,2001,1(3):181～193.
[25]Yorek MA. The role of oxidative stress in diabetic vascular and neural disease [J]. Free Radic Res ,2003 ,37 (5) :471-480.
[26]KONDO K,MATSUBARA T,NAKAMURA J, et al. Characteristic patterns of circadian variation in plasma catecholamine levels, blood pressure and heart rate variability in type 2 diabetic patients [J]. Diabet Med, 2002, 19 (5) : 359-365.
[27]丛丽,俞茂华,李益明,等.心肌胶原代谢变化在糖尿病心肌病变发生中作用的实验研究[J].中国临床康复, 2004 , 8 ( 9) :1655.
[28]Nishikawa N , Yamamoto K, Sakata Y, et al . Differential activation of matrix metalloproteinases in heart failure with and without ventricular dilatation[J]. Cardiovasc Res ,2003 ,57 (3):766-774.
[29]Zhang F, Li G, et al. Zhonghua Nei Ke Za Zhi. 2002,41(8):530-533
[30]Finck BN,Han X, Courtois M,et al.Proc Natl Acad Sci USA.2003, 100(3): 1226-1231 .
[31]Finck BN,Lehman JJ,Leone JC,et al.J Cha Invest.2002,109(1):121-130 .
[32]Puigserver P, Rhee J, Donovan J, et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 2003, 423: 550-5.
[33]Kawakami Y, Tsuda M, Takahashi S, et al. Transcriptional coactivator PGC-1alpha regulates chondrogenesis via association with Sox9. Proc Natl Acad Sci USA 2005, 102:2414-9.
[34]Kamei Y, Ohizumi H, Fujitani Y, et al. PPARgamma coactivator1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc Natl Acad Sci USA 2003,100:12378-83.
[35]Lin J, Tarr PT, Yang R, et al. PGC-1beta in the regulation of hepatic glucose and energy metabolism. J Biol Chem 2003, 278:30843-8.
[36]Spiegelman BM, Heinrich R. Biological control through regulated transcriptional coactivators. Cell. 2004, 119:157-67.
[37]Lin J, Yang R, Tarr PT, et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. Cell 2005, 120:261-73.
[38]Schreiber SN, Emter R, Hock MB, et al. The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)- induced mitochondrial biogenesis. Proc Natl Acad Sci U S A 2004, 101:6472-7.
[39]Wallberg AE, Yamamura S, Malik S, Spiegelman BM, Roeder RG. Coordination of p300-mediated chromatin remodeling and TRAP/mediator function through coactivator PGC-1alpha. Mol Cell 2003, 12:1137-49.
[40]Monsalve M, Wu Z, Adelmant G, Puigserver P, Fan M, Spiegelman BM. Direct coupling of transcription and mRNA processing through the thermogenic coactivator PGC-1. Mol Cell 2000, 6:307-16.
[41]Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP. Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest 2000, 106:847-56.
[42]Arany Z, He H, Lin J, et al. Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab 2005, 1:259-71.
[43]Huss JM, Kopp RP, Kelly DP. Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha. J Biol Chem 2002, 277:40265-74.
[44]Finck BN, Lehman JJ, Leone TC, et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 2002, 109:121-30.
[45]Sano M, Wang SC, Shirai M, et al. Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure. Embo J 2004, 23:3559-69.
[46]金朝阳,邹大进.游离脂肪酸致胰岛素抵抗的机制[J]. 1999. ed. 247.
[47]文重远,陈小琳.双重胰岛抵抗对糖尿病大鼠心肌能量代谢及心功能的影响[J]. 2005, 200.
[48]D D, DJ R. Emerging therapies targeting hing-density lipoprotein metabolism and revers cholesterol transport[J]. 2006. , 1140-50.
[49]李莲静,陈晓虎.罗格列酮对原发性高血压伴2型糖尿病患者血压的影响[J]。2007. 667-8.
[50]SK J, SY Y. Alpha-MSH decrease apoptosis in ischemic acute renal failure in rats:possible mechanism of this beneficial effect[J]. 2001, 1583.
[51]郭晓风,李秀丽.罗格列酮的药理学研究概况[J]. 2006, 138-9.
[52]TD W, WJ C. Effects of rosiglitazone on endothelial function, C-reactive protein, and components of the metabolic syndrome in nondiabetic patients with the metabolic syndrome[J]. 2004.
[53]M S, J W. Treatment with rosiglitazone reduces hyperinsulinemia and improves arterial elasticity in patients with type 2 diabetes mellitus[J]. 2003.
[54]DS C, L M. Peroxisome proliferator-activated receptorγligands increase release of nitric oxide from endothelial cells. 2003. 52-57.
[55]Y F, H I. Thiazolidinediones, peroxisome proliferator-activated receptor gamma agonists, regulate endothelial cell growth and secretion of vasoactive peptides[J]. 2001, 113-9.
[56]QN D, ME1 M. Structure,endothelial function, cell growth, and inflammation in blood vessels of angiotensinⅡ-infused rats: role of peroxisome proliferator- activated receptor-γ[J]. 2002. 2296-302.
[57]M I. RM T. Effect of peroxisome proliferator-activated receptor-αand -γactivators on vascular remodeling in endothelin-dependent hypertension[J]. 2003. 45-51.
[58]陆晓骅,鲍思蔚.罗格列酮对冠心病合并2型糖尿病患者IL-6、TNF-α的影响[J]. 2007. 891-2.
[59]Myazaki Y, Glass L. Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in TypeⅡdiabetic patients[J]. 2001, 2-10.
[60]AB, RS H, The effect of rosiglitazone on insulin sensitivity,lipolysis,and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes[J]. 2002, 797.
[61]邵建政.罗格列酮对2型糖尿病血浆脂代谢和C反应蛋白的影响[J].交通医学,2007.
[62]C J, T TA.PPARr agonists inhibit production of monocyte inflammatory cytokines[J]. 1998. 82-6.
[63]O G, S J.Atorvastatin activates PPAR-gamma and attenuates the inflam- matory response in human monocytes[J]. 2002. 58-62.
[64]Y T,Y K. Vascular inflammation is negatively autoregulated by interaction between CCAAT/enhancer-binding protein-delta and peroxisome proliferator- activated receptor-gamma[J].Circ Res, 2002, 91(5):427-433. 2002,427-33.
[65]JI B. The relation of markers of inflammation to the development of glucose disorders in the elderly[J]. 2001. ABRAJA L, 2384-9.
[66]丁健,陈海燕.罗格列酮对兔动脉粥样硬化心血管系统超微结构的影响[J]. 2008. 342-4.
[67]王莉,刘素筠.罗格列酮对STZ诱导的糖尿病大鼠大血管超微结构的影响[J]. 2007, 1074-7.
[68]E LR,S G. Expression and function of PPAR in rat and human vascular smooth muscle cells[J]. 2000. 1311-8.
[69]I I, K S.Expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary cultures of human vascular endothelial cells[J]. 1998. 370-4.
[70]范彩逢,李恩.罗格列酮对急性心肌梗死大鼠心肌细胞凋亡及其基因表达的影响[J]. 2008,183-5.
[71]陈海燕,李杰.罗格列酮对SHR大鼠降压作用和靶器官保护机制研究[J].中国老年学杂志. 2007,1970-3.
[72]汪涛,秦志平.罗格列酮对大鼠心肌梗死后心肌肥厚标志基因BNP影响[J]. 2007. 6-8.
[73]Franconi F, Seghieri G, Canu S, Straface E, Campesi I, Malorni W. Are the available experimental models of type 2 diabetes appropriate for a gender perspective[J]. Pharmacol Res 2008;57:6-18.
[74]Sahin K, Onderci M, Tuzcu M, et al. Effect of chromium on carbohydrate and lipid metabolism in a rat model of type 2 diabetes mellitus: the fat-fed, streptozotocin-treated rat[J]. Metabolism. 2007;56:1233-40.
[75]Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening[J]. Pharmacol Res 2005;52:313-20.
[76]Reed MJ, Meszaros K, Entes LJ, et al. A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat[J]. Metabolism 2000;49:1390-4.
[77]Zhao S, Chu Y, Zhang C, et al. Diet-induced central obesity and insulin resistance in rabbits[J]. J Anim Physiol Anim Nutr (Berl) 2008;92:105-11.
[78]Flanagan AM, Brown JL, Santiago CA, Aad PY, Spicer LJ, Spicer MT. High-fat diets promote insulin resistance through cytokine gene expression in growing female rats[J]. J Nutr Biochem 2008;19:505-13.
[79]Tanaka S, Hayashi T, Toyoda T, et al. High-fat diet impairs the effects of a single bout of endurance exercise on glucose transport and insulin sensitivity in rat skeletal muscle[J]. Metabolism 2007;56:1719-28.
[80]Sotnikova R, Skalska S, Okruhlicova L, et al. Changes in the function and ultrastructure of vessels in the rat model of multiple low dose streptozotocin-induced diabetes[J]. Gen Physiol Biophys 2006;25:289-302.
[81]Kim E, Sohn S, Lee M, Jung J, Kineman RD, Park S. Differential responses of the growth hormone axis in two rat models of streptozotocin- induced insulinopenic diabetes[J]. J Endocrinol 2006;188:263-70.
[82]Howarth FC, Qureshi A, Shahin A, Lukic ML. Effects of single high-dose and multiple low-dose streptozotocin on contraction and intracellular Ca2+ in ventricular myocytes from diabetes resistant and susceptible rats[J]. Mol Cell Biochem 2005;269:103-8.
[83]Kannan Y, Tokunaga M, Moriyama M, Kinoshita H, Nakamura Y. Beneficial effects of troglitazone on neutrophil dysfunction in multiple low-dose streptozotocin-induced diabetic mice[J]. Clin Exp Immunol 2004;137:263-71.
[84]Friesen NT, Buchau AS, Schott-Ohly P, Lgssiar A, Gleichmann H. Generation of hydrogen peroxide and failure of antioxidative responses in pancreatic islets of male C57BL/6 mice are associated with diabetes induced by multiple low doses of streptozotocin[J]. Diabetologia 2004;47:676-85.
[85]Jr Wright JR, Lacy PE. Synergistic effects of adjuvants, endotoxin, and fasting on induction of diabetes with multiple low doses of streptozocin in rats[J]. Diabetes 1988;37:112-8.
[86]Yu De-min ,Yu Pei. The consideration about the cardiovascular safety of rosiglitazone[J]. Journal of china prescribed drug, 2007, 7(64):51-53.
[87]Steven E, Nissen, Kathy Wolski. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes[J]. N Engl J Med, 2007,356(24):2457-2471.
[88]Nassirah Khandoudi, Philippe Delerive, Isabelle Berrebi Bertrand, et al. Rosiglitazone, a Peroxisome Proliferator Activated Receptor-γ, Inhibits the Jun NH2-Terminal Kinase/Activating Protein 1 Pathway and Protects the Heart From Ischemia/Reperfusion Injury[J]. Diabetes, 2002, 51: 1507-1514.
[89]Behzad Molavi, Jiawei Chen, and J. L. Mehta. Cardioprotective effects of rosiglitazone are associated with selective overexpression of type 2 angiotensin receptors and inhibition of p42/44 MAPK[J]. Am J Physiol Heart Circ Physiol, 2006, 291: H687-H693.
[90]Douglas G. Johns, Zhaohui Ao, Marianne Eybye, et al. Rosiglitazone Protects against Ischemia/Reperfusion-Induced Leukocyte Adhesion in the Zucker Diabetic Fatty Rat[J]. JPET 2005, 315(3): 1020-1027.
[91]Ni-Huiping Son, Tae-Sik Park, Haruyo Yamashita, etal. Cardiomyocyte expression of PPARγleads to cardiac dysfunction in mice[J]. The Journal of Clinical Investigation, 2007, 17(10):2791-2801
[92]Liang CHEN, Sai Ma, Long-xiao Wei, et al. Cardioprotective and antiarrhythmic effect of U50,488H in ischemia/reperfusion rat heart[J]. Heart vessel, 2007,22:335-344.
[93]Gao F,Yue TL, Shi DW, et al. p38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation[J] . Cadiovasc Res, 2002,53,414-422.
[94]Walker MJ, Curtis MJ, Hearse DJ, et al. The Lambeth Conventions guidelines for the study of arrhythmias in ischaemia infarction, and reperfusion[J]. Cardiovasc Res,1988,22:447-455.
[95]Joosen AM, Bakker AH, Kersten S, etal. The PPARgamma ligand rosiglitazone influences triacylglycerol metabolism in non-obese males, without increasing the transcriptional activity of PPARgamma in the subcutaneous adipose tissue[J]. Br J Nutr, 2008, 99(3):487-493.