Candido Riccardo, Allen Terri J, Lassila Markus, Cao Zemin, Thallas Vicki, Cooper Mark E, Jandeleit-Dahm Karin A
Vascular Division, Baker Heart Research Institute, PO Box 6492, Melbourne 8008, Victoria, Australia.
Circulation. 2004 Mar 30;109(12):1536-42. doi: 10.1161/01.CIR.0000124061.78478.94. Epub 2004 Mar 15.
It remains controversial whether specific blockade of the renin-angiotensin system confers superior antiatherosclerotic effects over other antihypertensive agents in diabetes. Therefore, the aim of this study was to compare equihypotensive doses of the angiotensin II subtype 1 (AT1) receptor blocker irbesartan with the calcium antagonist amlodipine on diabetes-induced plaque formation in the apolipoprotein E (apoE)-null mouse and to explore molecular and cellular mechanisms linked to vascular protection.
Diabetes was induced by injection of streptozotocin in 6-week-old apoE-null mice. Diabetic animals were randomized to no treatment, irbesartan, or amlodipine for 20 weeks. Diabetes was associated with an increase in plaque area and complexity in the aorta in association with a significant increase in aortic AT1 receptor expression, cellular proliferation, collagen content, macrophage- and alpha-smooth muscle actin-positive cell infiltration, as well as an increased expression of platelet-derived growth factor-B (PDGF-B), monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1). Irbesartan but not amlodipine treatment attenuated the development of atherosclerosis, collagen content, cellular proliferation, and macrophage infiltration as well as diabetes-induced AT1 receptor, PDGF-B, MCP-1, and VCAM-1 overexpression in the aorta despite similar blood pressure reductions by both treatments.
Diabetes-associated atherosclerosis is ameliorated by AT1 receptor blockade but not by calcium channel antagonism, providing further evidence for the vascular renin-angiotensin system playing a pivotal role in the development and acceleration of atherosclerosis in diabetes.
在糖尿病患者中，肾素 - 血管紧张素系统的特异性阻断是否比其他抗高血压药物具有更优越的抗动脉粥样硬化作用仍存在争议。因此，本研究的目的是比较血管紧张素II 1型（AT1）受体阻滞剂厄贝沙坦与钙拮抗剂氨氯地平在载脂蛋白E（apoE）基因敲除小鼠中对糖尿病诱导的斑块形成的等效降压剂量，并探索与血管保护相关的分子和细胞机制。
通过向6周龄的apoE基因敲除小鼠注射链脲佐菌素诱导糖尿病。将糖尿病动物随机分为不治疗组、厄贝沙坦组或氨氯地平组，治疗20周。糖尿病与主动脉斑块面积增加和复杂性增加相关，同时主动脉AT1受体表达、细胞增殖、胶原蛋白含量、巨噬细胞和α - 平滑肌肌动蛋白阳性细胞浸润显著增加，以及血小板衍生生长因子 - B（PDGF - B）、单核细胞趋化蛋白 - 1（MCP - 1）和血管细胞粘附分子 - 1（VCAM - 1）的表达增加。尽管两种治疗降低血压相似，但厄贝沙坦治疗而非氨氯地平治疗减轻了动脉粥样硬化的发展、胶原蛋白含量、细胞增殖和巨噬细胞浸润，以及糖尿病诱导的主动脉中AT1受体、PDGF - B、MCP - 1和VCAM - 1的过表达。
AT1受体阻断可改善糖尿病相关的动脉粥样硬化，而钙通道拮抗则不能，这为血管肾素 - 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提供了进一步证据。
