PPARs在不同周龄ApoE-/-小鼠心肌的表达及他汀干预的机制研究~1
|
摘要
目的:近年研究证明,心肌肥厚是临床上多种心血管疾病走向终末阶段的共同的病理生理基础。过氧化物酶体增殖物活化型受体(PPAR)α、β/δ和γ的活化可改善心肌肥厚。作为临床应用广泛的降低胆固醇药物,他汀已被证明有抑制心肌肥厚的作用,但是机制尚未明确。本课题组前期研究提示阿托伐他汀可以上调原代培养新生大鼠的心室肌细胞的PPARs,抑制心肌细胞肥大。载脂蛋白E基因敲除小鼠(ApoE-/-小鼠)虽已成为探讨动脉粥样硬化发病机制的常规模型,长期的胆固醇增高和主动脉粥样硬化同样可能引起心脏后负荷增加、心肌肥厚和心肌纤维化,但是关于其心脏改变报道较少。本研究旨在1.观察高胆固醇喂养的不同周龄ApoE-/-小鼠的心脏改变;2.观察PPARs在不同周龄ApoE-/-小鼠心肌中的表达及辛伐他汀的干预并探讨其分子机制。
方法:1.选用8周龄ApoE-/-小鼠36只,饲以含脂肪21%、胆固醇0.15%的“西方膳食”饲料喂养8周后即16周龄,随机被分为三组继续饲以“西方膳食”饲料喂养至24周龄组、32周龄组和40周龄组,每一周龄组为12只。每一周龄组再随机分为模型组6只和辛伐他汀干预组6只(25mg/kg/d),相同周龄的C57BL/6J小鼠设为对照。分别在24周龄、32周龄、40周龄结束时处死小鼠。2.观察不同周龄ApoE-/-小鼠模型组及辛伐他汀药物作用后,血清和心肌胆固醇水平、心肌抗氧化水平的变化;心脏病理切片HE染色观察心脏一般形态变化、Masson染色观察心肌胶原改变;苦味酸-天狼猩红染色并在偏光镜下观察Ⅰ、Ⅲ型胶原分布及其量的变化。3.Western blot观察24周龄、32周龄、40周龄ApoE-/-小鼠模型组及辛伐他汀药物作用后,蛋白酶MMP-9、Cathepsin S、PPARs蛋白表达的变化。4实时定量PCR观察24周龄、32周龄、40周龄ApoE-/-小鼠模型组及辛伐他汀药物作用后,MMP-9/TIMP-1、Cathepsin S/Cystatin C、PPARs的mRNA表达变化。
结果:1.24周龄、32周龄、40周龄ApoE-/-小鼠模型组血浆和心肌组织TC水平逐渐增高(P＜0.05);自16周起予辛伐他汀25mg/kg/d干预,24周龄、32周龄、40周龄他汀干预组的血浆和心肌组织TC水平较相同周龄模型组均显著下降(P＜0.05)。2.24周龄、32周龄、40周龄ApoE-/-小鼠模型组血浆NO和SOD含量逐渐降低,MDA水平逐渐增高(P＜0.05);辛伐他汀干预组NO和SOD含量高于相同周龄模型组(P＜0.05);而MDA的生成则显著低于相同周龄模型组(P＜0.01)。辛伐他汀可能增加ApoE-/-小鼠的抗氧化能力。3.HE染色显示ApoE-/-小鼠心脏左室壁平均厚度和心肌细胞的直径在24周龄、32周龄、40周龄逐渐增大(P＜0.05)。与相同周龄模型组相比,24周龄、32周龄、40周龄辛伐他汀干预组心肌细胞的直径显著减小(P＜0.05),40周龄辛伐他汀干预组左室壁平均厚度明显降低(P＜0.05)。4.光镜下观察24周龄、32周龄、40周龄ApoE-/-小鼠心肌胶原逐渐增多,表现为CVF和PVCA逐渐增加(P＜0.05);与相同周龄模型组相比,32周龄、40周龄辛伐他汀干预组CVF和PVCA明显降低(P＜0.05)。5.Western Blot结果提示,24周龄、32周龄、40周龄ApoE-/-小鼠模型组心肌MMP-9和Cathepsin S蛋白表达逐渐增多(P＜0.05);与相同周龄模型组相比,32周龄、40周龄辛伐他汀干预组MMP-9和Cathepsin S蛋白表达明显降低(P＜0.05)。24周龄、32周龄、40周龄ApoE-/-小鼠模型组心肌PPARα、γ蛋白表达逐渐下降(P＜0.05);与相同周龄模型组相比,32周龄、40周龄辛伐他汀上调PPARα、γ蛋白表达(P＜0.05)。6.Real time PCR结果提示,24周龄、32周龄、40周龄ApoE-/-小鼠模型组心肌MMP-9和Cathepsin S mRNA表达逐渐增多,TIMP-1的mRNA表达逐渐减少(P＜0.05);与相同周龄模型组相比,32周龄、40周龄辛伐他汀干预组MMP-9和Cathepsin S mRNA表达显著降低(P＜0.05);24周龄、32周龄、40周龄辛伐他汀干预组TIMP-1和CystatinC mRNA表达显著增加(P＜0.05)。24周龄、32周龄、40周龄ApoE-/-小鼠模型组心肌PPARα、γmRNA表达逐渐下降(P＜0.05);与相同周龄模型组相比,32周龄、40周龄辛伐他汀上调PPARα、γmRNA表达(P＜0.05)。
结论:本研究结果提示,随着ApoE-/-小鼠周龄增加,血浆胆固醇升高,脂质过氧化作用增强,MDA等毒性物质产生增多,SOD、NO抗氧化物质产生减少;同时动脉粥样硬化程度加深,可能引发心肌细胞肥大和心肌纤维化。辛伐他汀可以降低血浆和心肌组织胆固醇水平,增强心肌抗氧化能力,降低心肌MMP-9和Cathepsin S表达,增加TIMP-1和Cystatin C的表达,上调PPARα、γ蛋白和mRNA的表达,可能防治心肌重构。
Objective:Recent research has shown that cardiac hypertrophy is fundamental response of cardiac myocytes to various stimuli,which is associated with significantly increased risk of heart failure and malignant arrhythmia. ApoE-/-mice may occur myocardium remodeling with the development of atherosclerosis of coronary artery.Recently,it has been proved that peroxisome peroliferator activated-receptors(PPARs) are involved in prevention of cardiac hypertrophy,and statins exert their effect on up regulation of PPARs in primary cultures of cardiac myocytes.The purposes of this study were:1.to investigate the the dynamic changes in cardiac morphology and myocardial collagen in apoE-deficient(ApoE-/-) mice of different week in cholesterol-fed;2.To investigate the expression of PPARs in the myocardium of ApoE-/-mice of different weeks and the mechanism of the statin intervention.
Methods:Thirty six male apoE-deficient mice with eight week age were fed in high cholesterol feed,aged to 16 weeks,were randomized into three groups: twenty four week group(n=12),thirty two week group(n=12),forty week group (n=12),each group were randomized again into two groups:model group(n=6) and simvastatin intervention group(n=6),normal C57BL/6J mice were set as the control group.Serum cholesterol,low-density lipoprotein cholesterol(LDL-C), triglyceride,high-density lipoprotein cholesterol(HDL-C) concentrations were determined.Optical microscopy was adopted to assess the myocardial cells changes.To observe myocardial collagen with Masson dye,image analysis was performed with computer.Collagen specific dyeing and quantitative analysis was identificated by Picric-Sirius Red Polarimetry.Using Western blot,the MMP-9,Cathepsin S,PPARs expression was observed,the mRNA expression of MMP-9,Cathepsin S,PPARs was measured by real time polymerase chain reaction(PCR).
Results:1.As compared with the twenty four week group,total cholesterol,MDA, myocardial cells diameter and the content of myocardial collagen of thirty two and forty week group was significantly increased(P＜0.05),NO and SOD was significantly decreased(P＜0.05).2.Diameter of myocardial cell and the content of myocardial collagen were significantly decreased in simvastatin intervention group(P＜0.05),as the level of NO and SOD was significantly increased(P＜0.05).3.Compared with the model group,MMP-9,Cathepsin S expressions were significantly decreased in simvastatin treatment groups of thirty two week group and forty week group(P＜0.05),PPARα、γexpressions were significantly increased in simvastatin treatment groups of thirty two week group and forty week group(P＜0.05).
Conclusion:Diameter of myocardial cell and the content of myocardial collagen were significantly increased in apoE-deficient(apoE-/-) mice in cholesterol-fed with the progress of atherosclerosis and antioxidant capacity,simvastatin may reduce cardiac remodeling.
方法:1.选用8周龄ApoE-/-小鼠36只,饲以含脂肪21%、胆固醇0.15%的“西方膳食”饲料喂养8周后即16周龄,随机被分为三组继续饲以“西方膳食”饲料喂养至24周龄组、32周龄组和40周龄组,每一周龄组为12只。每一周龄组再随机分为模型组6只和辛伐他汀干预组6只(25mg/kg/d),相同周龄的C57BL/6J小鼠设为对照。分别在24周龄、32周龄、40周龄结束时处死小鼠。2.观察不同周龄ApoE-/-小鼠模型组及辛伐他汀药物作用后,血清和心肌胆固醇水平、心肌抗氧化水平的变化;心脏病理切片HE染色观察心脏一般形态变化、Masson染色观察心肌胶原改变;苦味酸-天狼猩红染色并在偏光镜下观察Ⅰ、Ⅲ型胶原分布及其量的变化。3.Western blot观察24周龄、32周龄、40周龄ApoE-/-小鼠模型组及辛伐他汀药物作用后,蛋白酶MMP-9、Cathepsin S、PPARs蛋白表达的变化。4实时定量PCR观察24周龄、32周龄、40周龄ApoE-/-小鼠模型组及辛伐他汀药物作用后,MMP-9/TIMP-1、Cathepsin S/Cystatin C、PPARs的mRNA表达变化。
结果:1.24周龄、32周龄、40周龄ApoE-/-小鼠模型组血浆和心肌组织TC水平逐渐增高(P＜0.05);自16周起予辛伐他汀25mg/kg/d干预,24周龄、32周龄、40周龄他汀干预组的血浆和心肌组织TC水平较相同周龄模型组均显著下降(P＜0.05)。2.24周龄、32周龄、40周龄ApoE-/-小鼠模型组血浆NO和SOD含量逐渐降低,MDA水平逐渐增高(P＜0.05);辛伐他汀干预组NO和SOD含量高于相同周龄模型组(P＜0.05);而MDA的生成则显著低于相同周龄模型组(P＜0.01)。辛伐他汀可能增加ApoE-/-小鼠的抗氧化能力。3.HE染色显示ApoE-/-小鼠心脏左室壁平均厚度和心肌细胞的直径在24周龄、32周龄、40周龄逐渐增大(P＜0.05)。与相同周龄模型组相比,24周龄、32周龄、40周龄辛伐他汀干预组心肌细胞的直径显著减小(P＜0.05),40周龄辛伐他汀干预组左室壁平均厚度明显降低(P＜0.05)。4.光镜下观察24周龄、32周龄、40周龄ApoE-/-小鼠心肌胶原逐渐增多,表现为CVF和PVCA逐渐增加(P＜0.05);与相同周龄模型组相比,32周龄、40周龄辛伐他汀干预组CVF和PVCA明显降低(P＜0.05)。5.Western Blot结果提示,24周龄、32周龄、40周龄ApoE-/-小鼠模型组心肌MMP-9和Cathepsin S蛋白表达逐渐增多(P＜0.05);与相同周龄模型组相比,32周龄、40周龄辛伐他汀干预组MMP-9和Cathepsin S蛋白表达明显降低(P＜0.05)。24周龄、32周龄、40周龄ApoE-/-小鼠模型组心肌PPARα、γ蛋白表达逐渐下降(P＜0.05);与相同周龄模型组相比,32周龄、40周龄辛伐他汀上调PPARα、γ蛋白表达(P＜0.05)。6.Real time PCR结果提示,24周龄、32周龄、40周龄ApoE-/-小鼠模型组心肌MMP-9和Cathepsin S mRNA表达逐渐增多,TIMP-1的mRNA表达逐渐减少(P＜0.05);与相同周龄模型组相比,32周龄、40周龄辛伐他汀干预组MMP-9和Cathepsin S mRNA表达显著降低(P＜0.05);24周龄、32周龄、40周龄辛伐他汀干预组TIMP-1和CystatinC mRNA表达显著增加(P＜0.05)。24周龄、32周龄、40周龄ApoE-/-小鼠模型组心肌PPARα、γmRNA表达逐渐下降(P＜0.05);与相同周龄模型组相比,32周龄、40周龄辛伐他汀上调PPARα、γmRNA表达(P＜0.05)。
结论:本研究结果提示,随着ApoE-/-小鼠周龄增加,血浆胆固醇升高,脂质过氧化作用增强,MDA等毒性物质产生增多,SOD、NO抗氧化物质产生减少;同时动脉粥样硬化程度加深,可能引发心肌细胞肥大和心肌纤维化。辛伐他汀可以降低血浆和心肌组织胆固醇水平,增强心肌抗氧化能力,降低心肌MMP-9和Cathepsin S表达,增加TIMP-1和Cystatin C的表达,上调PPARα、γ蛋白和mRNA的表达,可能防治心肌重构。
Objective:Recent research has shown that cardiac hypertrophy is fundamental response of cardiac myocytes to various stimuli,which is associated with significantly increased risk of heart failure and malignant arrhythmia. ApoE-/-mice may occur myocardium remodeling with the development of atherosclerosis of coronary artery.Recently,it has been proved that peroxisome peroliferator activated-receptors(PPARs) are involved in prevention of cardiac hypertrophy,and statins exert their effect on up regulation of PPARs in primary cultures of cardiac myocytes.The purposes of this study were:1.to investigate the the dynamic changes in cardiac morphology and myocardial collagen in apoE-deficient(ApoE-/-) mice of different week in cholesterol-fed;2.To investigate the expression of PPARs in the myocardium of ApoE-/-mice of different weeks and the mechanism of the statin intervention.
Methods:Thirty six male apoE-deficient mice with eight week age were fed in high cholesterol feed,aged to 16 weeks,were randomized into three groups: twenty four week group(n=12),thirty two week group(n=12),forty week group (n=12),each group were randomized again into two groups:model group(n=6) and simvastatin intervention group(n=6),normal C57BL/6J mice were set as the control group.Serum cholesterol,low-density lipoprotein cholesterol(LDL-C), triglyceride,high-density lipoprotein cholesterol(HDL-C) concentrations were determined.Optical microscopy was adopted to assess the myocardial cells changes.To observe myocardial collagen with Masson dye,image analysis was performed with computer.Collagen specific dyeing and quantitative analysis was identificated by Picric-Sirius Red Polarimetry.Using Western blot,the MMP-9,Cathepsin S,PPARs expression was observed,the mRNA expression of MMP-9,Cathepsin S,PPARs was measured by real time polymerase chain reaction(PCR).
Results:1.As compared with the twenty four week group,total cholesterol,MDA, myocardial cells diameter and the content of myocardial collagen of thirty two and forty week group was significantly increased(P＜0.05),NO and SOD was significantly decreased(P＜0.05).2.Diameter of myocardial cell and the content of myocardial collagen were significantly decreased in simvastatin intervention group(P＜0.05),as the level of NO and SOD was significantly increased(P＜0.05).3.Compared with the model group,MMP-9,Cathepsin S expressions were significantly decreased in simvastatin treatment groups of thirty two week group and forty week group(P＜0.05),PPARα、γexpressions were significantly increased in simvastatin treatment groups of thirty two week group and forty week group(P＜0.05).
Conclusion:Diameter of myocardial cell and the content of myocardial collagen were significantly increased in apoE-deficient(apoE-/-) mice in cholesterol-fed with the progress of atherosclerosis and antioxidant capacity,simvastatin may reduce cardiac remodeling.
引文
[1]LevyD,Garrison RJ,Savage DD,et al.Prognostic implications of ehcoeardiogarphically determined left ventricular mass in the Framingham heart study.N Engl J Med.1990,322(22):1561-1566.
[2]Morgan HE,Godron EE,Kira Y,et al.Biochemical mechanisms of cardiac hypertrophy.Annu Rev Physiol.1987,49:533-543.
[3]Cohn JN.Structural basis for heart failure.Ventricular remodeling and its pharmacological inhibition[J].Circulation,1995,91(10):2504-2507.
[4]Weber KT,Brilla CG.Pathological hypertrophy and cardiac interstitium:fibrosis and renin-angiotensin-aldosterone system[J].Circulation,1991,83:1849-1865.
[5]Sehaper JA,Speiser B.The extracellular matrix in the failing human heart[J].Basic Res Cardio,1992,87(Supply):303-309.
[6]Borg TK,Burgess ML.Holding It all together:organization and function(s)of the extracellular matrix in the heart[J].Heart Failure,1993,9:230-238.
[7]Tyagi SC.Proteinases and myocardial extracellular matrix turnover[J].Mol Cell Bioehem,1997,168:1-12.
[8]Breslow JL.Mouse models of atherosclerosis[J].Science,1996,272:685-688.
[9]Nakashima Y,Plump AS,Raines EW,et al.ApoE-Deficient Mice Develop Lesions of All Phases of Atherosclerosis Throughout the Arterial Tree[J].Arteriosclerosis,Thrombosis and Vascular Biology,1994,14:133-40.
[10]Wang YX.Cardiovascular functional phenotypes and pharmacological responses in apolipoprotein E deficient mice[J].Neurobiol Aging,2005,26:309-16.
[11]Peloueh V,DixonI MC,Golfman L,et al.Role of extracellular matrix proteins in heart function[J].Mol Cell Biochem,1994,129:101-120.
[12]Van der Rest M,Garrone R.Collagen family of proteins[J].FASEB J,1991,5:2814-2823.
[13]Tyagi SC,Matsubara L,Weber KT,et al.Direct extraction estimation of collagenases activity by zymography in microquantities of rat myocardium and uierus.Clin Biochem.1993,26:191-198.
[14]Cleutjeiis JPM,Kandala JC,Guarda E,et al.Regulation of collagen degradation in the rat myocardium after infarction.J Mol Cell Cardial,1994,27;1281-1292.
[15]Coker MS,Thomas CV,Doscher MA.Matrix metalloproteinase expression and activity in adult ventricular myocytes:influence of basermen membrane adhension.Circulation.1997,96(suppl):Ⅰ-689.
[16]吴艳,王毅,杨刚毅.组织蛋白酶K与骨质疏松的研究进展.中国骨质疏松杂志,2006,12:522-524
[17]Shi GP,Sukhova GK,Grubb A,Ducharme A,Rhode LH,Lee RT,Ridker PM,Libby P,Chapman HA.Cystatin C deficiency in human atherosclerosis and aortic aneurysms.J Clin Invest,1999,104:1191-1197.
[18]Sukhova GK,Shi GP.Do cathepsins play a role in abdominal aortic aneurysm pathogenesis? Ann N Y Acad Sci,2006,1085:161-169.
[19]Neve BP,Fruchart JC,Staels B,et al.Role of the peroxisome proliferator-activated receptors(PPAR) in atherosclerosis.Biochem-Pharmacol.2000,15,60(8):1245-1250.
[20]Wayman N,Ellis B,Tiedemann C.Ligands of theperoxisome proliferator-activated receptor-PPAR-a reduce myocardial infarct size.Med.Sci.Monit.2002,8(7):BR243-BR247.
[21]Mark Gurnell,John M.Wentworth,et al.A Dominant-negative Peroxisome Proliferator-activated Receptor(PPAR)Mutant Is a Constitutive Repressor and Inhibits PPAR-mediated Adipogenesis.J Biol Chem,2000,275:5754-5759.
[22]Wayman NS,Hattori Y,McDonald MC,et al.Legends of the peroxisome proliferator-activated receptors(PPAR-gamma and PPAR-alpha)reduces myocardial infarct size.FASEB J.2002;16:1027-40.
[23]Shiomi T,Tsutsui H,Hayashidani S,et al Pioglitazone,a peroxisome proliferator-activated receptor-gamma agonist,attenuates left ventricular remodeling and failure after experimental myocardial infarction.Circulation,2002;106:3126-3132.
[24]Xu Y,Gen M,Lu L,Fox J,et al.PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs.PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs. Am J Physiol Heart Circ Physiol.2005;288:H1314-23.
[25]Frantz S,Hu K,Widder J,et al.Peroxosome-proliferator activated receptor agonism and left ventricular remodeling in mice with chronic myocardial infarction.Br J Pharmacol.2004;141:9-14.
[26]Ogata T, Miyauchi T, Sakai S, et al. Stimulation of peroxisome-proliferator-activated receptor alpha(PPAR alpha)attenuates cardiac fibrosis and endothelin-1 production in pressure-overloaded rat hearts.Clin Sci(Lond),2002;103 Suppl 48:284S-288S.
[27]Diep QN,Benkirane K,Amiri F,et al.PPAR alpha activator fenofibrate inhibits myocardial inflammation and fibrosis in angiotensin II-infused rats.J Mol Cell Cardiol,2004;36:295-304.
[28]Chen K,Chen J,Li D,et al.Angiotensin II regulation of collagen type I expression in cardiac fibroblasts:modulation by PPAR-gamma ligand pioglitazone.Hypertension,2004;44:655-61.
[29]Tyagi SC,Rodriguez W,Patel AM,et al.Hyperhomocysteinemic diabetic cardiomyopathy:oxidative stress,remodeling,and endothelial-myocyte uncoupling.J Cardiovasc Pharmacol Ther,2005;10:1-10.
[1]LevyD,Garrison RJ,Savage DD,et al.Pomgostic implications of ehcoeardiogarphically determined left venrtieular mass in the Farmingham heart study.N Engl J Med.1990,322(22):1561-1566.
[2]Breslow JL.Mouse models of atherosclerosis[J].Science,1996,272:685-688.
[3]Nakashima Y,Plump AS,Raines EW,et al.ApoE-Deficient Mice Develop Lesions of All Phases of Atherosclerosis Throughout the Arterial Tree[J].Arteriosclerosis,Thrombosis and Vascular Biology,1994,14:133-40.
[4]Kuwahara F,Kai H,Tokuda K,et al.Transforminggrowth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats.Circulation,2002,106:130-135.
[5]Li YY,Feng YQ,Kadokami T,et al.Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor-αcan be modulated by anti-tumor necrosis factor-αtherapy[J].Proc Natl Acad Sci USA,2000,97(23):12746-12751.
[6]Thomas C V,Coker M L,Zellner J L,et al.Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy.Circulation,1998,97:1708-1715.
[7]殷照初 李永青 吴秀山 基质金属蛋白酶与心肌重塑.生命科学研究2004 June,8(2):43-48.
[8]彭龙云 高修仁 麦炜颐等 基质金属蛋白酶与心肌间质重构.国外医学内科学分册 2002 Aut,29(9):388-394.
[9]Weber KT,Brilla CG.Pathological hypertrophy and cardiac interstitium:fibrosis and renin-angiotensin-aldosterone system[J].Circulation,1991,83:1849-1865.
[10]Sehaper JA,Speiser B.The extracellular matrix in the failing human heart[J].Basic Res Cardio,1992,87(Supply):303-309.
[11]Borg TK,Burgess ML.Holding It all together:organization and function(s)of the extracellular matrix in the heart[J].Heart Failure,1993,9:230-238.
[12]Tyagi SC.Proteinases and myocardial extracellular matrix turnover[J].Mol Cell Bioehem,1997,168:1-12.
[13]Zhang SH,Reddiok RL,Piedrahita JA,et al.Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E[J].Seience,1992,258(5081):468-471.
[14]Wang YX.Cardiovascular functional phenotypes and pharmacological responses in apolipoprotein E deficient mice[J].Neurobiol Aging,2005,26,:309-16.
[15]Vincelette J,Martin-McNulty B,Vergona R,et al.Reduced cardiac functional reserve in apolipoprotein E knockout mice[J].Transl Res,2006,148:30-6.
[16]Hartley CJ,Reddy AK,Madala S,et al.Hemodynamic changes in apolipoprotein E-knockout mice[J].Am J Physiol Heart Circ Physiol,2000,279,:H2326-34.
[17]常青,张莉,贾琴,等.家兔冠状动脉粥样硬化形成过程中心脏的形态重塑[J].解剖学报,2006,37:552-556.
[18]刘剑刚,董国菊,史大卓,等.载脂蛋白E基因敲除小鼠不同周龄动脉粥样硬化的病理变化[J].中国动脉硬化杂志,2005,13:689-692.
[1]LevyD,Garrison RJ,Savage DD,et al.Prognostic implications of echoeardiogarphically determined left ventricular mass in the Framingham heart study.N Engl J Med.1990,322(22):1561-1566.
[2]Morgan HE,Godron EE,Kira Y,et al.Biochemical mechanisms of cardiac hypertrophy.Annu Rev Physiol.1987,49:533-543.
[3]Peloueh V,DixonI MC,Golfman L,et al.Role of extracellular matrix proteins in heart function[J].Mol Cell Biochem,1994,129:101-120.
[4]Van der Rest M,Garrone R.Collagen family of proteins[J].FASEB J,1991,5:2814-2823.
[5]Querejeta R, Varo N, Lopez B, et al.Serum carboxy terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart didease.Circulation,2000,101:1729-1735.
[6]Kobori H, Lchihara A, Miyashits Y, et al.Local renninangiotensin system contributes to hyperthyroidism-induced cardial hypertrophy.J Endocrinol, 1999,160:43-47.
[7]Hara K, Kobayashi N, Nakano S, et al.Effect of TCV116 on endothelin-1 and PDGFA-chain expression in angiotensin II-induced hypertensive rats.Hypertens Res,2001,24:55-64.
[8]Diez C, Nestler M, Friedrich U, et al.Down-regulation of Akt/PKB in senescent cardie fibroblasts impairs PDGF-induced cell proliferation.Cardiovasc Res, 2001,49:731-740.
[9]Kolpakov V,Gordon D,Kulik TJ.Nitric oxide-generating compounds inhibit totall protein and collagen synthesis in cultured vascular smooth muscle cells[J].Circ Res,1995,76(2):305-309.
[10]Li YY, Feng YQ, Kadokami T,et al.Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti -tumor necrosis factor alpha therapy[J].Proc Natl Acad Sci U S A,2000 ,97(23):12746-51.
[11]Peterson JT,Li H,Dillon L,et al.Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarctedrat[J].Cardiovasc Res, 2000,46:307-315.
[12]Liu J,Sukhova GK,Sun JS,Xu WH,Libby P,Shi GP.Lysosomal cysteine proteases in atherosclerosis.Arterioscler Thromb Vase Biol,2004,24:1359-1366
[13]Shi GP,Sukhova GK,Grubb A,Ducharme A,Rhode LH,Lee RT,Ridker PM,Libby P,Chapman HA.Cystatin C deficiency in human atherosclerosis and aortic aneurysms.J Clin Invest,1999,104:1191-1197
[14]Mark Gurnell,John M.Wentworth,et al.A Dominant-negative Peroxisome Proliferator-activated Receptor(PPAR)Mutant Is a Constitutive Repressor and Inhibits PPAR-mediated Adipogenesis.J Biol Chem,2000,275:5754-5759.
[15]Planavila A,Laguna JC,Vazquez-Carrera M.Atorvastatin improves peroxisome proliferator-activated receptor signaling in cardiac hypertrophy by preventing nuclear factor-kappa B activation.Biochimica et Biophysica Acta,2005;1687:76-83.
[16]Irukayama-Tomobe Y,Miyauchi T,Sakai S,et al.Endothelin-1-induced cardiac hypertrophy is inhibited by activation of peroxisome proliferator-activated receptor-alpha partly via blockade of c-Jun NH2-terminal kinase pathway.Circulation,2004;109:904-10.
[17]Masayuki Aasakawa,Hiroyuki Takano T,Toshino Nagai etal.Perxisome Proliferator-Activated Recptorγplays a critical Role inhibition of cardial Hypertrophy in vivtro and in vivo.Circulation,2002;105:1240-1246.
[18]Ogata T,Miyauchi T,Sakai S,et al.Stimulation of peroxisome-proliferator-activated receptor alpha(PPAR alpha)attenuates cardiac fibrosis and endothelin-1 production in pressure-overloaded rat hearts.Clin Sci(Lond),2002;103 Suppl 48:284S-288S.
[19]Chen K,Chen J,Li D,et al.Angiotensin II regulation of collagen type I expression in cardiac fibroblasts modulation by PPAR-gamma ligand pioglitazone.Hypertension,2004;44:655-61.
[20]Tyagi SC,Rodriguez W,Patel AM,et al.Hyperhomocystememic diabetic cardiomyopathy :oxidative stress,remodeling,and endothelial-my ocyte uncoupling.J Cardiovasc Pharmacol Ther,2005;10:l-10.
[21]Wayman NS,Hattori Y,McDonald MC,et al.Legends of the peroxisome proliferator-activated receptors(PPAR-gamma and PPAR-alpha)reduces myocardial infarct size.FASEB J.2002;16:1027-40.
[22]Shiomi T,Tsutsui H,Hayashidani S,et al Pioglitazone,a peroxisome proliferator-activated receptor-gamma agonist,attenuates left ventricular remodeling and failure after experimental myocardial infarction.Circulation,2002;106:3126-3132.
[23]Xu Y,Gen M,Lu L,Fox J,et al.PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs.PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs. Am J Physiol Heart Circ Physiol.2005;288:H1314-23.
[24]Frantz S,Hu K,Widder J,et al.Peroxosome-proliferator activated receptor agonism and left ventricular remodeling in mice with chronic myocardial infarction.Br J Pharmacol.2004;141:9-14.
[25]Zhang SH, Reddiok RL, Piedrahita JA, et al. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E[J].Seience,1992,258(5081):468-471.
[26]Breslow JL.Mouse models of atherosclerosis[J].Science,1996,272:685-688.
[27]Nakashima Y,Plump AS,Raines EW,et al.ApoE-Deficient Mice Develop Lesions of All Phases of Atherosclerosis Throughout the Arterial Tree[J].Arteriosclerosis,Thrombosis and Vascular Biology.1994,14:133-40
[28]刘剑刚,董国菊,史大卓等.载脂蛋白E基因敲除小鼠不同周龄动脉粥样硬化的病理变化[J].中国动脉硬化杂志,2005,13:689-692.
[29]Wang YX.Cardiovascular functional phenotypes and pharmacological responses in apolipoprotein E deficient mice[J].Neurobiol Aging,2005,26,:309-16.
[30]Vincelette J,Martin-McNulty B,Vergona R,et al.Reduced cardiac functional reserve in apolipoprotein E knockout mice[J].Transl Res,2006,148:30-6.
[31]Hartley CJ,Reddy AK,Madala S,et al.Hemodynamic changes in apolipoprotein E-knockout mice[J].Am J Physiol Heart Circ Physiol.2000,279:H2326-34.
[32]谢晓华,刘宁,刘秀华等.高胆固醇饮食诱导的心肌纤维化及其发生机制[J].解放军医学杂志,2003,28(12):1096-1097.
[33]常青,张莉,贾琴等.家兔冠状动脉粥样硬化形成过程中心脏的形态重塑[J].解剖学报,2006,37:552-556.
[34]常培叶,刘志跃,赵平.动脉粥样硬化兔血管和心室重构的研究.中国老年学杂志,2008,22:2190-2192.
[35]Kolpakov V,Gordon D,Kulik TJ.Nitric oxide-generating compounds inhibit totall protein and collagen synthesis in cultured vascular smooth muscle cells[J].Circ Res,1995,76(2):305-309.
[1]Kenneth J.Rodgers;Deborah J.Watkins;Alastair L.Miller;Peter Y.Chan;Sharada Karanam;William H.Brissette;Clive J.Long;Chris topher L.Jackson.Destabilizing Role of Cathepsin S in Murine Atherosclerotic Plaques.Arteriosclerosis,Thrombosis,and Vascular Biology,2006,2(4):851-856.
[2]Marianna Papaspyridonos;Alberto Smith;Kevin G.Burnand;Peter Taylor;Soundrie Padayachee;Keith E.Suckling;Christian H.James;David R.Greaves;Lisa Patel.Novel Candidate Genes in Unstable Areas of Human Atherosclerotic Plaques.Arteriosclerosis,Thrombosis,and Vascular Biology,2006,26:1837.
[3]郭爱桃,石怀银,韦立新,孙璐.人冠状动脉粥样硬化斑块内细胞成分与斑块稳定性的关系.第四军医大学学报,2005,26:2093-2096.
[4]Sofia Jormsj(o|¨),Dirk M.Wuttge,Allan Sirsj(o|¨),Carl Whatling,Anders Hamsten,Sten Stemme and Per Eriksson.Differential Expression of Cysteine and Aspartic Proteases during Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice.American Journal of Pathology,2002,161:939-945.
[5]Newby AC.Dual role of matrix metalloproteinases(matrixins) in intimal thickening and atherosclerotic plaque rupture.Physiol Rev,2005,85:1-31.
[6]吴艳,王毅,杨刚毅.组织蛋白酶K与骨质疏松的研究进展.中国骨质疏松杂志,2006,12:522-524.
[7]Wun-Shaing W.Chang1,Hsin-Ru Wu,Chi-Tai Yeh,Cheng-Wen Wu,and Jang-Yang Chang.Lysosomal Cysteine Proteinase Cathepsin S as a Potential Target for Anti-Cancer Therapy.Journal of Cancer Molecules,2007,3:5-14.
[8]Yoshifuji H,Umehara H,Maruyama H,Itoh M,Tanaka M,Kawabata D,Fujii T,Mimori T.Amelioration of experimental arthritis by a calpain-inhibitory compound:regulation of cytokine production by E-64-d in vivo and in vitro.Int Immunol,2005,17(10):1327-1336.
[9]Liu J,Sukhova GK,Sun JS,Xu WH,Libby P,Shi GP.Lysosomal cysteine proteases in atherosclerosis.Arterioscler Thromb Vase Biol,2004,24:1359-1366.
[10]Sukhova GK,Shi GP.Do cathepsins play a role in abdominal aortic aneurysm pathogenesis? Ann N Y Acad Sci,2006,1085:161-169.
[11]Sukhova GK,Shi GP,Simon DI,Chapman HA,Libby P.Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells.J Clin Invest,1998,102:576-583.
[12]Li Z,Yasuda Y,Li W,Bogyo M,Katz N,Gordon RE,Fields GB,Bromme D.Regulation of collagenase activities of human cathepsins by glycosaminoglycans.JBiolChem,2004,279:5470-5479.
[13]Satu Helske,Suvi Syva'ranta,Ken A.Lindstedt,Jani Lappalainen,Katariina O~¨ o~¨rni,Mikko I.Ma~¨yra~¨npa~¨a~¨,Jyri Lornmi,Heikki Turto,Kalervo Werkkala,Markku Kupari,Petri T.Kovanen.Increased Expression of Elastolytic Cathepsins S,K,and V and Their Inhibitor Cystatin C in Stenotic Aortic Valves.Arterioscler Thromb Vase Biol,2006,26:1791-1798.
[14]Jian Liu,Galina K.Sukhov ,Jin-Tian Yang ,Jiusong Sun,Likun Ma,An Ren,Wei-Hua Xu,Huanxiang Fu,Gregory M.Dolganov ,Chengcheng Hu,Peter Libby,Guo-Ping Shi.Cathepsin L expression and regulation in human abdominal aortic aneurysm,atherosclerosis,and vascular cells.Atherosclerosis,2006,184:302-311.
[15]Oorni K,Sneck M,Bromme D,Pentikainen MO,Lindstedt KA,Mayranpaa M,Aitio H,Kovanen PT.Cysteine protease cathepsin F is expressed in human atherosclerotic lesions,is secreted by cultured macrophages,and modifies low density lipoprotein particles in vitro.J Biol Chem,2004,279:34776-34784.
[16]Liu J,Sukhova GK,Yang JT,Sun J,Ma L,Ren A,Xu WH,Fu H,Dolganov GM,Hu C,Libby P,Shi GP.Cathepsin L expression and regulation in human abdominal aortic aneurysm,atherosclerosis,and vascular cells.Atherosclerosis,2006 ,184:302-11.
[17]Jaffer FA,Kim DE,Quinti L,Tung CH,Aikawa E,Pande AN,Kohler RH,Shi GP,Libby P,Weissleder R.Optical visualization of cathepsin K activity in atherosclerosis with a novel,protease-activatable fluorescence sensor.Circulation,2007,115:2292-2298.
[18]Jormsjo S,Wuttge DM,Sirsjo A,Whatling C,Hamsten A,Stemme S,Eriksson P.Differential expression of cysteine and aspartic proteases during progression of atherosclerosis in apolipoprotein E-deficient mice.Am J Pathol,2002,161:939-945.
[19]Sukhova GK,Zhang Y,Pan JH,Wada Y,Yamamoto T,Naito M,Kodama T,Tsimikas S,Witztum JL,Lu ML,Sakara Y,Chin MT,Libby P,Shi GP.Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice.J Clin Invest,2003,111:897-906.
[20]Cheng XW,Kuzuya M,Sasaki T,Arakawa K,Kanda S,Sumi D,Koike T,Maeda K,Tamaya-Mori N,Shi GP,Saito N,Iguchi A.Increased expression of elastolytic cysteine proteases,cathepsins S and K,in the neointima of balloon-injured rat carotid arteries.Am J Pathol,2004,164:243-251.
[21]Burns-Kurtis CL,Olzinski AR,Needle S,Fox JH,Capper EA,Kelly FM,McQueney MS,Romanic AM.Cathepsin S expression is up-regulated following balloon angioplasty in the hypercholesterolemic rabbit. Cardiovasc Res,2004,62:610-620.
[22]Shi GP,Sukhova GK,Kuzuya M,Ye Q,Du J,Zhang Y,Pan JH,Lu ML,Cheng XW,Iguchi A,Perrey S,Lee AM,Chapman HA,Libby P.Deficiency of the cysteine protease cathepsin S impairs microvessel growth.Circ Res,2003,92:493-500.
[23]Lutgens E,Lutgens SP,Faber BC,Heeneman S,Gijbels MM,de Winther MP,Frederik P,van der Made I,Daugherty A,Sijbers AM,Fisher A,Long CJ,Saftig P,Black D,Daemen MJ,Cleutjens KB.Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation.Circulation,2006,113:98-107.
[24]Kitamoto S,Sukhova GK,Sun J,Yang M,Libby P,Love V,Duramad P,Sun C,Zhang Y,Yang X,Peters C,Shi GP.Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice.Circulation,2007,115:2065-75.
[25]Reddy VY,Zhang QY,Weiss SJ.Pericellular mobilization of the tissue-destructive cysteine proteases,cathepsin B,L,and S,by human monocyte-derived macrophages.Proc Natl Acad Sci U S A,1995,92:3849-3853.
[26]Cheng XW,Kuzuya M,Nakamura K,Di Q,Liu Z,Sasaki T,Kanda S,Jin H,Shi GP,Murohara T,Yokota M,Iguchi A.Localization of cysteine protease,cathepsin S,to the surface of vascular smooth muscle cells by association with integrin alphanubeta3.Am J Pathol,2006,168:685-694.
[27]Shi GP,Sukhova GK,Grubb A,Ducharme A,Rhode LH,Lee RT,Ridker PM,Libby P,Chapman HA.Cystatin C deficiency in human atherosclerosis and aortic aneurysms.J Clin Invest,1999,104:1191-1197.
[28]Bengtsson E,To F,Hakansson,A.Grubb,L.Branen,J.Nilsson,and S. Jovinge.Lack of the Cysteine Protease Inhibitor Cystatin C Promotes Atherosclerosis in Apolipoprotein E-Deficient Mice.Arterioscler.Thromb.Vasc.Bio,2005,25:2151-2156.
[29]Bengtsson E,Fang To,Grubb A,et al.Absence of the prote as e inhibitor cystatin C in inflammatory cells results in larger plaque area in plaque regression of ApoE-deficient mice[J].Atherosclerosis,2005,180:45-53.
[30]Sukhova GK,Wang B,Libby P,Pan JH,Zhang Y,Grubb A,Fang K,Chapman HA,Shi GP.Cystatin C deficiency increases elastic lamina degradation and aortic dilatation in apolipoprotein E-null mice.Circ Res,2005,96:368-375.
[31]Liu J,Ma L,Yang J,Ren A,Sun Z,Yan G,Sun J,Fu H,Xu W,Hu C,Shi GP.Increased serum cathepsin S in patients with atherosclerosis and diabetes. Atherosclerosis,2006,186:411-419.
[32]Lutgens E,van Suylen RJ,Faber BC,Gijbels MJ,Eurlings PM,Bijnens AP,Cleutjens KB,Heeneman S,Daemen MJ.Atherosclerotic plaque rupture:local or systemic process? Arterioscler Thromb Vase Biol,2003,23:2123-2130.
[2]Morgan HE,Godron EE,Kira Y,et al.Biochemical mechanisms of cardiac hypertrophy.Annu Rev Physiol.1987,49:533-543.
[3]Cohn JN.Structural basis for heart failure.Ventricular remodeling and its pharmacological inhibition[J].Circulation,1995,91(10):2504-2507.
[4]Weber KT,Brilla CG.Pathological hypertrophy and cardiac interstitium:fibrosis and renin-angiotensin-aldosterone system[J].Circulation,1991,83:1849-1865.
[5]Sehaper JA,Speiser B.The extracellular matrix in the failing human heart[J].Basic Res Cardio,1992,87(Supply):303-309.
[6]Borg TK,Burgess ML.Holding It all together:organization and function(s)of the extracellular matrix in the heart[J].Heart Failure,1993,9:230-238.
[7]Tyagi SC.Proteinases and myocardial extracellular matrix turnover[J].Mol Cell Bioehem,1997,168:1-12.
[8]Breslow JL.Mouse models of atherosclerosis[J].Science,1996,272:685-688.
[9]Nakashima Y,Plump AS,Raines EW,et al.ApoE-Deficient Mice Develop Lesions of All Phases of Atherosclerosis Throughout the Arterial Tree[J].Arteriosclerosis,Thrombosis and Vascular Biology,1994,14:133-40.
[10]Wang YX.Cardiovascular functional phenotypes and pharmacological responses in apolipoprotein E deficient mice[J].Neurobiol Aging,2005,26:309-16.
[11]Peloueh V,DixonI MC,Golfman L,et al.Role of extracellular matrix proteins in heart function[J].Mol Cell Biochem,1994,129:101-120.
[12]Van der Rest M,Garrone R.Collagen family of proteins[J].FASEB J,1991,5:2814-2823.
[13]Tyagi SC,Matsubara L,Weber KT,et al.Direct extraction estimation of collagenases activity by zymography in microquantities of rat myocardium and uierus.Clin Biochem.1993,26:191-198.
[14]Cleutjeiis JPM,Kandala JC,Guarda E,et al.Regulation of collagen degradation in the rat myocardium after infarction.J Mol Cell Cardial,1994,27;1281-1292.
[15]Coker MS,Thomas CV,Doscher MA.Matrix metalloproteinase expression and activity in adult ventricular myocytes:influence of basermen membrane adhension.Circulation.1997,96(suppl):Ⅰ-689.
[16]吴艳,王毅,杨刚毅.组织蛋白酶K与骨质疏松的研究进展.中国骨质疏松杂志,2006,12:522-524
[17]Shi GP,Sukhova GK,Grubb A,Ducharme A,Rhode LH,Lee RT,Ridker PM,Libby P,Chapman HA.Cystatin C deficiency in human atherosclerosis and aortic aneurysms.J Clin Invest,1999,104:1191-1197.
[18]Sukhova GK,Shi GP.Do cathepsins play a role in abdominal aortic aneurysm pathogenesis? Ann N Y Acad Sci,2006,1085:161-169.
[19]Neve BP,Fruchart JC,Staels B,et al.Role of the peroxisome proliferator-activated receptors(PPAR) in atherosclerosis.Biochem-Pharmacol.2000,15,60(8):1245-1250.
[20]Wayman N,Ellis B,Tiedemann C.Ligands of theperoxisome proliferator-activated receptor-PPAR-a reduce myocardial infarct size.Med.Sci.Monit.2002,8(7):BR243-BR247.
[21]Mark Gurnell,John M.Wentworth,et al.A Dominant-negative Peroxisome Proliferator-activated Receptor(PPAR)Mutant Is a Constitutive Repressor and Inhibits PPAR-mediated Adipogenesis.J Biol Chem,2000,275:5754-5759.
[22]Wayman NS,Hattori Y,McDonald MC,et al.Legends of the peroxisome proliferator-activated receptors(PPAR-gamma and PPAR-alpha)reduces myocardial infarct size.FASEB J.2002;16:1027-40.
[23]Shiomi T,Tsutsui H,Hayashidani S,et al Pioglitazone,a peroxisome proliferator-activated receptor-gamma agonist,attenuates left ventricular remodeling and failure after experimental myocardial infarction.Circulation,2002;106:3126-3132.
[24]Xu Y,Gen M,Lu L,Fox J,et al.PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs.PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs. Am J Physiol Heart Circ Physiol.2005;288:H1314-23.
[25]Frantz S,Hu K,Widder J,et al.Peroxosome-proliferator activated receptor agonism and left ventricular remodeling in mice with chronic myocardial infarction.Br J Pharmacol.2004;141:9-14.
[26]Ogata T, Miyauchi T, Sakai S, et al. Stimulation of peroxisome-proliferator-activated receptor alpha(PPAR alpha)attenuates cardiac fibrosis and endothelin-1 production in pressure-overloaded rat hearts.Clin Sci(Lond),2002;103 Suppl 48:284S-288S.
[27]Diep QN,Benkirane K,Amiri F,et al.PPAR alpha activator fenofibrate inhibits myocardial inflammation and fibrosis in angiotensin II-infused rats.J Mol Cell Cardiol,2004;36:295-304.
[28]Chen K,Chen J,Li D,et al.Angiotensin II regulation of collagen type I expression in cardiac fibroblasts:modulation by PPAR-gamma ligand pioglitazone.Hypertension,2004;44:655-61.
[29]Tyagi SC,Rodriguez W,Patel AM,et al.Hyperhomocysteinemic diabetic cardiomyopathy:oxidative stress,remodeling,and endothelial-myocyte uncoupling.J Cardiovasc Pharmacol Ther,2005;10:1-10.
[1]LevyD,Garrison RJ,Savage DD,et al.Pomgostic implications of ehcoeardiogarphically determined left venrtieular mass in the Farmingham heart study.N Engl J Med.1990,322(22):1561-1566.
[2]Breslow JL.Mouse models of atherosclerosis[J].Science,1996,272:685-688.
[3]Nakashima Y,Plump AS,Raines EW,et al.ApoE-Deficient Mice Develop Lesions of All Phases of Atherosclerosis Throughout the Arterial Tree[J].Arteriosclerosis,Thrombosis and Vascular Biology,1994,14:133-40.
[4]Kuwahara F,Kai H,Tokuda K,et al.Transforminggrowth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats.Circulation,2002,106:130-135.
[5]Li YY,Feng YQ,Kadokami T,et al.Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor-αcan be modulated by anti-tumor necrosis factor-αtherapy[J].Proc Natl Acad Sci USA,2000,97(23):12746-12751.
[6]Thomas C V,Coker M L,Zellner J L,et al.Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy.Circulation,1998,97:1708-1715.
[7]殷照初 李永青 吴秀山 基质金属蛋白酶与心肌重塑.生命科学研究2004 June,8(2):43-48.
[8]彭龙云 高修仁 麦炜颐等 基质金属蛋白酶与心肌间质重构.国外医学内科学分册 2002 Aut,29(9):388-394.
[9]Weber KT,Brilla CG.Pathological hypertrophy and cardiac interstitium:fibrosis and renin-angiotensin-aldosterone system[J].Circulation,1991,83:1849-1865.
[10]Sehaper JA,Speiser B.The extracellular matrix in the failing human heart[J].Basic Res Cardio,1992,87(Supply):303-309.
[11]Borg TK,Burgess ML.Holding It all together:organization and function(s)of the extracellular matrix in the heart[J].Heart Failure,1993,9:230-238.
[12]Tyagi SC.Proteinases and myocardial extracellular matrix turnover[J].Mol Cell Bioehem,1997,168:1-12.
[13]Zhang SH,Reddiok RL,Piedrahita JA,et al.Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E[J].Seience,1992,258(5081):468-471.
[14]Wang YX.Cardiovascular functional phenotypes and pharmacological responses in apolipoprotein E deficient mice[J].Neurobiol Aging,2005,26,:309-16.
[15]Vincelette J,Martin-McNulty B,Vergona R,et al.Reduced cardiac functional reserve in apolipoprotein E knockout mice[J].Transl Res,2006,148:30-6.
[16]Hartley CJ,Reddy AK,Madala S,et al.Hemodynamic changes in apolipoprotein E-knockout mice[J].Am J Physiol Heart Circ Physiol,2000,279,:H2326-34.
[17]常青,张莉,贾琴,等.家兔冠状动脉粥样硬化形成过程中心脏的形态重塑[J].解剖学报,2006,37:552-556.
[18]刘剑刚,董国菊,史大卓,等.载脂蛋白E基因敲除小鼠不同周龄动脉粥样硬化的病理变化[J].中国动脉硬化杂志,2005,13:689-692.
[1]LevyD,Garrison RJ,Savage DD,et al.Prognostic implications of echoeardiogarphically determined left ventricular mass in the Framingham heart study.N Engl J Med.1990,322(22):1561-1566.
[2]Morgan HE,Godron EE,Kira Y,et al.Biochemical mechanisms of cardiac hypertrophy.Annu Rev Physiol.1987,49:533-543.
[3]Peloueh V,DixonI MC,Golfman L,et al.Role of extracellular matrix proteins in heart function[J].Mol Cell Biochem,1994,129:101-120.
[4]Van der Rest M,Garrone R.Collagen family of proteins[J].FASEB J,1991,5:2814-2823.
[5]Querejeta R, Varo N, Lopez B, et al.Serum carboxy terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart didease.Circulation,2000,101:1729-1735.
[6]Kobori H, Lchihara A, Miyashits Y, et al.Local renninangiotensin system contributes to hyperthyroidism-induced cardial hypertrophy.J Endocrinol, 1999,160:43-47.
[7]Hara K, Kobayashi N, Nakano S, et al.Effect of TCV116 on endothelin-1 and PDGFA-chain expression in angiotensin II-induced hypertensive rats.Hypertens Res,2001,24:55-64.
[8]Diez C, Nestler M, Friedrich U, et al.Down-regulation of Akt/PKB in senescent cardie fibroblasts impairs PDGF-induced cell proliferation.Cardiovasc Res, 2001,49:731-740.
[9]Kolpakov V,Gordon D,Kulik TJ.Nitric oxide-generating compounds inhibit totall protein and collagen synthesis in cultured vascular smooth muscle cells[J].Circ Res,1995,76(2):305-309.
[10]Li YY, Feng YQ, Kadokami T,et al.Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti -tumor necrosis factor alpha therapy[J].Proc Natl Acad Sci U S A,2000 ,97(23):12746-51.
[11]Peterson JT,Li H,Dillon L,et al.Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarctedrat[J].Cardiovasc Res, 2000,46:307-315.
[12]Liu J,Sukhova GK,Sun JS,Xu WH,Libby P,Shi GP.Lysosomal cysteine proteases in atherosclerosis.Arterioscler Thromb Vase Biol,2004,24:1359-1366
[13]Shi GP,Sukhova GK,Grubb A,Ducharme A,Rhode LH,Lee RT,Ridker PM,Libby P,Chapman HA.Cystatin C deficiency in human atherosclerosis and aortic aneurysms.J Clin Invest,1999,104:1191-1197
[14]Mark Gurnell,John M.Wentworth,et al.A Dominant-negative Peroxisome Proliferator-activated Receptor(PPAR)Mutant Is a Constitutive Repressor and Inhibits PPAR-mediated Adipogenesis.J Biol Chem,2000,275:5754-5759.
[15]Planavila A,Laguna JC,Vazquez-Carrera M.Atorvastatin improves peroxisome proliferator-activated receptor signaling in cardiac hypertrophy by preventing nuclear factor-kappa B activation.Biochimica et Biophysica Acta,2005;1687:76-83.
[16]Irukayama-Tomobe Y,Miyauchi T,Sakai S,et al.Endothelin-1-induced cardiac hypertrophy is inhibited by activation of peroxisome proliferator-activated receptor-alpha partly via blockade of c-Jun NH2-terminal kinase pathway.Circulation,2004;109:904-10.
[17]Masayuki Aasakawa,Hiroyuki Takano T,Toshino Nagai etal.Perxisome Proliferator-Activated Recptorγplays a critical Role inhibition of cardial Hypertrophy in vivtro and in vivo.Circulation,2002;105:1240-1246.
[18]Ogata T,Miyauchi T,Sakai S,et al.Stimulation of peroxisome-proliferator-activated receptor alpha(PPAR alpha)attenuates cardiac fibrosis and endothelin-1 production in pressure-overloaded rat hearts.Clin Sci(Lond),2002;103 Suppl 48:284S-288S.
[19]Chen K,Chen J,Li D,et al.Angiotensin II regulation of collagen type I expression in cardiac fibroblasts modulation by PPAR-gamma ligand pioglitazone.Hypertension,2004;44:655-61.
[20]Tyagi SC,Rodriguez W,Patel AM,et al.Hyperhomocystememic diabetic cardiomyopathy :oxidative stress,remodeling,and endothelial-my ocyte uncoupling.J Cardiovasc Pharmacol Ther,2005;10:l-10.
[21]Wayman NS,Hattori Y,McDonald MC,et al.Legends of the peroxisome proliferator-activated receptors(PPAR-gamma and PPAR-alpha)reduces myocardial infarct size.FASEB J.2002;16:1027-40.
[22]Shiomi T,Tsutsui H,Hayashidani S,et al Pioglitazone,a peroxisome proliferator-activated receptor-gamma agonist,attenuates left ventricular remodeling and failure after experimental myocardial infarction.Circulation,2002;106:3126-3132.
[23]Xu Y,Gen M,Lu L,Fox J,et al.PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs.PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs. Am J Physiol Heart Circ Physiol.2005;288:H1314-23.
[24]Frantz S,Hu K,Widder J,et al.Peroxosome-proliferator activated receptor agonism and left ventricular remodeling in mice with chronic myocardial infarction.Br J Pharmacol.2004;141:9-14.
[25]Zhang SH, Reddiok RL, Piedrahita JA, et al. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E[J].Seience,1992,258(5081):468-471.
[26]Breslow JL.Mouse models of atherosclerosis[J].Science,1996,272:685-688.
[27]Nakashima Y,Plump AS,Raines EW,et al.ApoE-Deficient Mice Develop Lesions of All Phases of Atherosclerosis Throughout the Arterial Tree[J].Arteriosclerosis,Thrombosis and Vascular Biology.1994,14:133-40
[28]刘剑刚,董国菊,史大卓等.载脂蛋白E基因敲除小鼠不同周龄动脉粥样硬化的病理变化[J].中国动脉硬化杂志,2005,13:689-692.
[29]Wang YX.Cardiovascular functional phenotypes and pharmacological responses in apolipoprotein E deficient mice[J].Neurobiol Aging,2005,26,:309-16.
[30]Vincelette J,Martin-McNulty B,Vergona R,et al.Reduced cardiac functional reserve in apolipoprotein E knockout mice[J].Transl Res,2006,148:30-6.
[31]Hartley CJ,Reddy AK,Madala S,et al.Hemodynamic changes in apolipoprotein E-knockout mice[J].Am J Physiol Heart Circ Physiol.2000,279:H2326-34.
[32]谢晓华,刘宁,刘秀华等.高胆固醇饮食诱导的心肌纤维化及其发生机制[J].解放军医学杂志,2003,28(12):1096-1097.
[33]常青,张莉,贾琴等.家兔冠状动脉粥样硬化形成过程中心脏的形态重塑[J].解剖学报,2006,37:552-556.
[34]常培叶,刘志跃,赵平.动脉粥样硬化兔血管和心室重构的研究.中国老年学杂志,2008,22:2190-2192.
[35]Kolpakov V,Gordon D,Kulik TJ.Nitric oxide-generating compounds inhibit totall protein and collagen synthesis in cultured vascular smooth muscle cells[J].Circ Res,1995,76(2):305-309.
[1]Kenneth J.Rodgers;Deborah J.Watkins;Alastair L.Miller;Peter Y.Chan;Sharada Karanam;William H.Brissette;Clive J.Long;Chris topher L.Jackson.Destabilizing Role of Cathepsin S in Murine Atherosclerotic Plaques.Arteriosclerosis,Thrombosis,and Vascular Biology,2006,2(4):851-856.
[2]Marianna Papaspyridonos;Alberto Smith;Kevin G.Burnand;Peter Taylor;Soundrie Padayachee;Keith E.Suckling;Christian H.James;David R.Greaves;Lisa Patel.Novel Candidate Genes in Unstable Areas of Human Atherosclerotic Plaques.Arteriosclerosis,Thrombosis,and Vascular Biology,2006,26:1837.
[3]郭爱桃,石怀银,韦立新,孙璐.人冠状动脉粥样硬化斑块内细胞成分与斑块稳定性的关系.第四军医大学学报,2005,26:2093-2096.
[4]Sofia Jormsj(o|¨),Dirk M.Wuttge,Allan Sirsj(o|¨),Carl Whatling,Anders Hamsten,Sten Stemme and Per Eriksson.Differential Expression of Cysteine and Aspartic Proteases during Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice.American Journal of Pathology,2002,161:939-945.
[5]Newby AC.Dual role of matrix metalloproteinases(matrixins) in intimal thickening and atherosclerotic plaque rupture.Physiol Rev,2005,85:1-31.
[6]吴艳,王毅,杨刚毅.组织蛋白酶K与骨质疏松的研究进展.中国骨质疏松杂志,2006,12:522-524.
[7]Wun-Shaing W.Chang1,Hsin-Ru Wu,Chi-Tai Yeh,Cheng-Wen Wu,and Jang-Yang Chang.Lysosomal Cysteine Proteinase Cathepsin S as a Potential Target for Anti-Cancer Therapy.Journal of Cancer Molecules,2007,3:5-14.
[8]Yoshifuji H,Umehara H,Maruyama H,Itoh M,Tanaka M,Kawabata D,Fujii T,Mimori T.Amelioration of experimental arthritis by a calpain-inhibitory compound:regulation of cytokine production by E-64-d in vivo and in vitro.Int Immunol,2005,17(10):1327-1336.
[9]Liu J,Sukhova GK,Sun JS,Xu WH,Libby P,Shi GP.Lysosomal cysteine proteases in atherosclerosis.Arterioscler Thromb Vase Biol,2004,24:1359-1366.
[10]Sukhova GK,Shi GP.Do cathepsins play a role in abdominal aortic aneurysm pathogenesis? Ann N Y Acad Sci,2006,1085:161-169.
[11]Sukhova GK,Shi GP,Simon DI,Chapman HA,Libby P.Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells.J Clin Invest,1998,102:576-583.
[12]Li Z,Yasuda Y,Li W,Bogyo M,Katz N,Gordon RE,Fields GB,Bromme D.Regulation of collagenase activities of human cathepsins by glycosaminoglycans.JBiolChem,2004,279:5470-5479.
[13]Satu Helske,Suvi Syva'ranta,Ken A.Lindstedt,Jani Lappalainen,Katariina O~¨ o~¨rni,Mikko I.Ma~¨yra~¨npa~¨a~¨,Jyri Lornmi,Heikki Turto,Kalervo Werkkala,Markku Kupari,Petri T.Kovanen.Increased Expression of Elastolytic Cathepsins S,K,and V and Their Inhibitor Cystatin C in Stenotic Aortic Valves.Arterioscler Thromb Vase Biol,2006,26:1791-1798.
[14]Jian Liu,Galina K.Sukhov ,Jin-Tian Yang ,Jiusong Sun,Likun Ma,An Ren,Wei-Hua Xu,Huanxiang Fu,Gregory M.Dolganov ,Chengcheng Hu,Peter Libby,Guo-Ping Shi.Cathepsin L expression and regulation in human abdominal aortic aneurysm,atherosclerosis,and vascular cells.Atherosclerosis,2006,184:302-311.
[15]Oorni K,Sneck M,Bromme D,Pentikainen MO,Lindstedt KA,Mayranpaa M,Aitio H,Kovanen PT.Cysteine protease cathepsin F is expressed in human atherosclerotic lesions,is secreted by cultured macrophages,and modifies low density lipoprotein particles in vitro.J Biol Chem,2004,279:34776-34784.
[16]Liu J,Sukhova GK,Yang JT,Sun J,Ma L,Ren A,Xu WH,Fu H,Dolganov GM,Hu C,Libby P,Shi GP.Cathepsin L expression and regulation in human abdominal aortic aneurysm,atherosclerosis,and vascular cells.Atherosclerosis,2006 ,184:302-11.
[17]Jaffer FA,Kim DE,Quinti L,Tung CH,Aikawa E,Pande AN,Kohler RH,Shi GP,Libby P,Weissleder R.Optical visualization of cathepsin K activity in atherosclerosis with a novel,protease-activatable fluorescence sensor.Circulation,2007,115:2292-2298.
[18]Jormsjo S,Wuttge DM,Sirsjo A,Whatling C,Hamsten A,Stemme S,Eriksson P.Differential expression of cysteine and aspartic proteases during progression of atherosclerosis in apolipoprotein E-deficient mice.Am J Pathol,2002,161:939-945.
[19]Sukhova GK,Zhang Y,Pan JH,Wada Y,Yamamoto T,Naito M,Kodama T,Tsimikas S,Witztum JL,Lu ML,Sakara Y,Chin MT,Libby P,Shi GP.Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice.J Clin Invest,2003,111:897-906.
[20]Cheng XW,Kuzuya M,Sasaki T,Arakawa K,Kanda S,Sumi D,Koike T,Maeda K,Tamaya-Mori N,Shi GP,Saito N,Iguchi A.Increased expression of elastolytic cysteine proteases,cathepsins S and K,in the neointima of balloon-injured rat carotid arteries.Am J Pathol,2004,164:243-251.
[21]Burns-Kurtis CL,Olzinski AR,Needle S,Fox JH,Capper EA,Kelly FM,McQueney MS,Romanic AM.Cathepsin S expression is up-regulated following balloon angioplasty in the hypercholesterolemic rabbit. Cardiovasc Res,2004,62:610-620.
[22]Shi GP,Sukhova GK,Kuzuya M,Ye Q,Du J,Zhang Y,Pan JH,Lu ML,Cheng XW,Iguchi A,Perrey S,Lee AM,Chapman HA,Libby P.Deficiency of the cysteine protease cathepsin S impairs microvessel growth.Circ Res,2003,92:493-500.
[23]Lutgens E,Lutgens SP,Faber BC,Heeneman S,Gijbels MM,de Winther MP,Frederik P,van der Made I,Daugherty A,Sijbers AM,Fisher A,Long CJ,Saftig P,Black D,Daemen MJ,Cleutjens KB.Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation.Circulation,2006,113:98-107.
[24]Kitamoto S,Sukhova GK,Sun J,Yang M,Libby P,Love V,Duramad P,Sun C,Zhang Y,Yang X,Peters C,Shi GP.Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice.Circulation,2007,115:2065-75.
[25]Reddy VY,Zhang QY,Weiss SJ.Pericellular mobilization of the tissue-destructive cysteine proteases,cathepsin B,L,and S,by human monocyte-derived macrophages.Proc Natl Acad Sci U S A,1995,92:3849-3853.
[26]Cheng XW,Kuzuya M,Nakamura K,Di Q,Liu Z,Sasaki T,Kanda S,Jin H,Shi GP,Murohara T,Yokota M,Iguchi A.Localization of cysteine protease,cathepsin S,to the surface of vascular smooth muscle cells by association with integrin alphanubeta3.Am J Pathol,2006,168:685-694.
[27]Shi GP,Sukhova GK,Grubb A,Ducharme A,Rhode LH,Lee RT,Ridker PM,Libby P,Chapman HA.Cystatin C deficiency in human atherosclerosis and aortic aneurysms.J Clin Invest,1999,104:1191-1197.
[28]Bengtsson E,To F,Hakansson,A.Grubb,L.Branen,J.Nilsson,and S. Jovinge.Lack of the Cysteine Protease Inhibitor Cystatin C Promotes Atherosclerosis in Apolipoprotein E-Deficient Mice.Arterioscler.Thromb.Vasc.Bio,2005,25:2151-2156.
[29]Bengtsson E,Fang To,Grubb A,et al.Absence of the prote as e inhibitor cystatin C in inflammatory cells results in larger plaque area in plaque regression of ApoE-deficient mice[J].Atherosclerosis,2005,180:45-53.
[30]Sukhova GK,Wang B,Libby P,Pan JH,Zhang Y,Grubb A,Fang K,Chapman HA,Shi GP.Cystatin C deficiency increases elastic lamina degradation and aortic dilatation in apolipoprotein E-null mice.Circ Res,2005,96:368-375.
[31]Liu J,Ma L,Yang J,Ren A,Sun Z,Yan G,Sun J,Fu H,Xu W,Hu C,Shi GP.Increased serum cathepsin S in patients with atherosclerosis and diabetes. Atherosclerosis,2006,186:411-419.
[32]Lutgens E,van Suylen RJ,Faber BC,Gijbels MJ,Eurlings PM,Bijnens AP,Cleutjens KB,Heeneman S,Daemen MJ.Atherosclerotic plaque rupture:local or systemic process? Arterioscler Thromb Vase Biol,2003,23:2123-2130.