Background— 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.

Methods and Results— 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 α-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.

Conclusions— 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.