替米沙坦对ApoE基因敲除小鼠主动脉粥样硬化斑块稳定性的影响
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摘要
目的评估血管紧张素受体1型(AT1)拮抗剂替米沙坦对载脂蛋白E (ApoE)基因敲除小鼠主动脉粥样硬化斑块稳定性的影响。方法选取30只ApoE小鼠并随机分为3组,13周高脂饮食后,替米沙坦组[12.01 mg/(kg·d)]、阿托伐他汀组[3 mg/(kg·d)]以及对照组(蒸馏水)继续饲养13周后处死,取小鼠主动脉根部的3个横切面,分别行HE染色、Movat染色以及免疫组织化学染色法观察动脉粥样硬化斑块内部成分。结果干预13周后,替米沙坦组和阿托伐他汀组主动脉斑块/内膜面积比值分别为28%、22%,均明显低于对照组的36%,差异均有统计学意义(P <0.05)。替米沙坦组和阿托伐他汀组易损指数分别为1.12和0.91,均明显低于对照组的2.67,差异均有统计学意义(P <0.05)。结论替米沙坦能显著抑制动脉粥样硬化的发生,稳定动脉粥样硬化斑块,可能与改变斑块的成分有关。
Objective The aim of this study was to evaluate whether treatment with the angiotensin receptor type 1(AT1)-antagonist telmisartan affects the plaque stability in the apolipoprotein E(apoE)-deficient mice,and explore the possible mechanism.Methods After 13 weeks of high-fat diet,30 apoE-deficient mice were randomized into telmisartan group,atorvastatin group,and control group,10 mice per group.The mice received the treatment with telmisartan 12.01 mg/(kg·d)in telmisartan group,atorvastatin 3 mg/(kg·d)in atorvastatin group,or distilled water in control group for an additional 13 weeks accompanied by a high-fat diet.Then the mice were sacrificed at the end of experiment.Cross sections of aortic roots were prepared and stained with Hematoxylin and Eosin(HE)staining,modified Movat pentachrome stain,or immunohistochemistry stain,respectively.Results After 13 weeks of treatment,the ratios of atherosclerotic lesions area to aorta intima area were 28%and 20%in the telmisartan group and atorvastatin group,respectively,which were significantly lower than that in control group(36%,both P <0.05).The vulnerability index were also significantly decreased in the telmisartan group and atorvastatin group(1.12 and 0.91,respectively),as compared with that in the control group(2.67,both P <0.05).Conculsion These results suggested that telmisartan could significantly inhibited the development of atherosclerosis and stabilized atherosclerotic plaque in apoE-deficient mice,which may be related to the alteration of plaque components.
Objective The aim of this study was to evaluate whether treatment with the angiotensin receptor type 1(AT1)-antagonist telmisartan affects the plaque stability in the apolipoprotein E(apoE)-deficient mice,and explore the possible mechanism.Methods After 13 weeks of high-fat diet,30 apoE-deficient mice were randomized into telmisartan group,atorvastatin group,and control group,10 mice per group.The mice received the treatment with telmisartan 12.01 mg/(kg·d)in telmisartan group,atorvastatin 3 mg/(kg·d)in atorvastatin group,or distilled water in control group for an additional 13 weeks accompanied by a high-fat diet.Then the mice were sacrificed at the end of experiment.Cross sections of aortic roots were prepared and stained with Hematoxylin and Eosin(HE)staining,modified Movat pentachrome stain,or immunohistochemistry stain,respectively.Results After 13 weeks of treatment,the ratios of atherosclerotic lesions area to aorta intima area were 28%and 20%in the telmisartan group and atorvastatin group,respectively,which were significantly lower than that in control group(36%,both P <0.05).The vulnerability index were also significantly decreased in the telmisartan group and atorvastatin group(1.12 and 0.91,respectively),as compared with that in the control group(2.67,both P <0.05).Conculsion These results suggested that telmisartan could significantly inhibited the development of atherosclerosis and stabilized atherosclerotic plaque in apoE-deficient mice,which may be related to the alteration of plaque components.
引文
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[13]FUKUI K,YAMADA H,MATSUBARA H.Pathophysiological role of tissue renin-angiotensin-aldo sterone system(RAAS)in human atherosclerosis[J].Nihon Rinsho,2012,70(9):1556-1561.
[14]NATARAJAN R,CAI Q.Monocyte retention in the pathology of atherosclerosis[J].Future Cardiol,2005,1(3):331-340.
[15]GE J,CHIRILLO F,SCHWEDTMANN J,et al.Screening of ruptured plaques in patients with coronary artery disease by intravascular ultrasound[J].Heart,1999,81:621-627.
[16]GAIA S,MINGYI W,ROBEERT M,et al.Rat aortic MCP-1 and its receptor CCR2increase with age and alter vascular smooth muscle cell function[J].Arterioslcer Thromb Vasc Boil,2004,24(8):1397.
[2]NAGHAVI M,LIBBY P,FALK E,et al.From vulnerable plaque to vulnerable patient:a call for new definitions and risk assessment strategies:PartⅠ[J].Circulation,2003,108:1664-1672.
[3]BRASIER A R,RECIONS A,ELEDRISI M S.Vascular inflammation and the renin-angiontensin system[J].Arterioscler Thromb Vasc Biol,2002,22(8):1257-1266.
[4]GROTHUSEN C,BLEY S,SELLE T,et al.Combined effects of HMG-CoA-reductase inhibition and renin-angiotensin system blockade on experimental atherosclerosis[J].Atherosclerosis,2005,182:57-69.
[5]JOHNSON J,CARSON K,WILLIAMS H,et al.Plaque rupture after short periods of fat feeding in the apolipoprotein E-knockout mouse:model characterization and effects of pravastatin treatment[J].Circulation,2005,111:1422-1430.
[6]ZHOU MX,XU H,PAN L,et al.Rosiglitazone promotes atherosclerotic plaque stability in fat-fed ApoE-Knockout mice[J].European Journal of Pharmacology,2008,590:297-302.
[7]SUZUKI H,KURIHARA Y,TAKEYA M,et al.A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection[J].Nature,1997,86:292-296.
[8]李莉,翟同均,陈融,等.Movat五色套染法的改进及应用[J].临床与实验病理学杂志,2002,8(6):660-662.
[9]ZAMAN A G,HELFT G,WORTHLEY S G,et al.The role of plaque rupture and thrombosis in coronary artery disease[J].Atheroselerosis,2000,149:251-266.
[10]YUSUF S,SLEIGHT P,POGUE J,et al.The heart outcomes prevention evaluation study investigators.Effects of an angiotensinconverting-enzyme inhibitor,ramipril,on death from cardiovascular causes,myocardial infaraction,and stroke in high-risk patients[J].N Engl J Med,2000,342:145-153.
[11]FOX K M.The European trial on reduction of cardiac events with perindopril in stable coronary artery disease investigators.Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease:randomised,double-blind,placebo-controlled,multicentre trial(the EUROPA study)[J].Lancet,2003,362:782-788.
[12]KJELDSEN S E,DAHLOF B,DEVEREUX R B,et al.Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy:a losartan intervention for endpoint reduction(LIFE)substudy[J].JAMA,2002,288(12):1491-1498.
[13]FUKUI K,YAMADA H,MATSUBARA H.Pathophysiological role of tissue renin-angiotensin-aldo sterone system(RAAS)in human atherosclerosis[J].Nihon Rinsho,2012,70(9):1556-1561.
[14]NATARAJAN R,CAI Q.Monocyte retention in the pathology of atherosclerosis[J].Future Cardiol,2005,1(3):331-340.
[15]GE J,CHIRILLO F,SCHWEDTMANN J,et al.Screening of ruptured plaques in patients with coronary artery disease by intravascular ultrasound[J].Heart,1999,81:621-627.
[16]GAIA S,MINGYI W,ROBEERT M,et al.Rat aortic MCP-1 and its receptor CCR2increase with age and alter vascular smooth muscle cell function[J].Arterioslcer Thromb Vasc Boil,2004,24(8):1397.