Candido Riccardo, Jandeleit-Dahm Karin A, Cao Zemin, Nesteroff Stefan P, Burns Wendy C, Twigg Stephen M, Dilley Rodney J, Cooper Mark E, Allen Terri J
Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg West, Australia.
Circulation. 2002 Jul 9;106(2):246-53. doi: 10.1161/01.cir.0000021122.63813.32.
Atherosclerosis is a major complication of diabetes, but the mechanisms by which diabetes promotes macrovascular disease have not been fully delineated. Although several animal studies have demonstrated that inhibition of ACE results in a decrease in the development of atherosclerotic lesions, information about the potential benefits of these agents on complex and advanced atherosclerotic lesions as observed in long-term diabetes is lacking. The aim of this study was to evaluate whether treatment with the ACE inhibitor perindopril affects diabetes-induced plaque formation in the apolipoprotein E (apoE)-deficient mouse.
Diabetes was induced by injection of streptozotocin in 6-week-old apoE-deficient mice. Diabetic animals received treatment with perindopril (4 mg x kg(-1) x d(-1)) or no treatment for 20 weeks. Nondiabetic apoE-deficient mice were used as controls. Induction of diabetes was associated with a 4-fold increase in plaque area compared with nondiabetic animals. This accelerated atherosclerosis was associated with a significant increase in aortic ACE expression and activity and connective tissue growth factor and vascular cell adhesion molecule-1 expression. Perindopril treatment inhibited the development of atherosclerotic lesions and diabetes-induced ACE, connective tissue growth factor, and vascular cell adhesion molecule-1 overexpression in the aorta.
The activation of the local renin-angiotensin system in the diabetic aorta and the reduction in atherosclerosis with ACE inhibitor treatment provides further evidence that the renin-angiotensin system plays a pivotal role in the development and acceleration of atherosclerosis in diabetes.
动脉粥样硬化是糖尿病的主要并发症，但糖尿病促进大血管疾病的机制尚未完全阐明。尽管多项动物研究表明，抑制血管紧张素转换酶（ACE）可减少动脉粥样硬化病变的发展，但对于这些药物对长期糖尿病中观察到的复杂和晚期动脉粥样硬化病变的潜在益处的信息仍很缺乏。本研究的目的是评估使用ACE抑制剂培哚普利治疗是否会影响载脂蛋白E（apoE）缺乏小鼠中糖尿病诱导的斑块形成。
通过向6周龄的apoE缺乏小鼠注射链脲佐菌素诱导糖尿病。糖尿病动物接受培哚普利（4 mg·kg⁻¹·d⁻¹）治疗或不治疗20周。非糖尿病的apoE缺乏小鼠用作对照。与非糖尿病动物相比，糖尿病的诱导与斑块面积增加4倍相关。这种加速的动脉粥样硬化与主动脉ACE表达和活性以及结缔组织生长因子和血管细胞黏附分子-1表达的显著增加有关。培哚普利治疗抑制了动脉粥样硬化病变的发展以及糖尿病诱导的主动脉中ACE、结缔组织生长因子和血管细胞黏附分子-1的过表达。
糖尿病主动脉中局部肾素-血管紧张素系统的激活以及ACE抑制剂治疗使动脉粥样硬化减轻，这进一步证明肾素-血管紧张素系统在糖尿病动脉粥样硬化的发生和加速发展中起关键作用。
