Angiotensin Receptor Blockade With Candesartan Attenuates Atherosclerosis, Plaque Disruption, and Macrophage Accumulation Within the Plaque in a Rabbit Model

Abstract

Background-Little is known about whether direct angiotensin receptor blockade can reduce atherosclerosis and plaque disruption. This study evaluated the effect of angiotensin receptor blockade on both the development of atherosclerosis and the disruption of plaque in a modified Constantinides animal model. Methods and Results-Twenty-eight New Zealand White rabbits underwent aortic balloon injury followed by a 1% cholesterol diet for 8 weeks. Thirteen rabbits received candesartan at 0.5 mg · kg Ϫ1 · d Ϫ1 beginning 2 days before aortic balloon injury and continued for the total 8 weeks of the cholesterol diet. The rabbits were then pharmacologically triggered and humanely killed, and their aortas were analyzed. The degree of atherosclerosis was determined by intima-media ratio of the infrarenal portion of the aorta. The frequency of intra-aortic thrombosis, a measure of plaque disruption, and the percentages of macrophage area and collagen-staining area of the plaque were determined. Candesartan-treated rabbits had less atherosclerosis (intima-media infrarenal aorta ratio of 1.18Ϯ0.08 versus 1.57Ϯ0.08[meanϮSEM] for the placebo group, PϽ0.001); fewer thrombi (3 of 13 versus 11 of 15; PϽ0.05); lower percentage area of macrophages to total plaque (18.8Ϯ2.7% versus 27Ϯ2.5%, PϽ0.05); and higher collagen to total plaque area (45Ϯ3% versus 35Ϯ2%, PϽ0.01).Conclusions-These results demonstrate that angiotensin receptor blockade attenuates the degree of atherosclerosis and reduces both plaque disruption and macrophage accumulation while increasing collagen deposition in the aortas of this animal model.

A robust rabbit model of human atherosclerosis and atherothrombosis

“…However, these studies did not establish the effect of such interventions on plaque disruption. We have previously demonstrated that an angiotensin receptor blocker attenuated atherosclerosis and reduced plaque disruption in a rabbit model of endothelial denudation followed by cholesterol feeding and pharmacological triggering for thrombosis (57). In this study, the rabbits received candesartan beginning 2 days before aortic balloon injury and continued for the 8 weeks of the cholesterol diet.…”

Telmisartan Increases the Permeability of Endothelial Cells through Zonula Occludens-1

“…Angiotensin receptor-1 blockers (ARBs) have been used to treat atherosclerosis in both animal models and humans. 1,2) Recently, it has been found that the ARB telmisartan has an interesting structural resemblance to the insulin sensitizer pioglitazone, a thiazolidinedione ligand of the peroxisome proliferator-activated receptor gamma (PPARg) which has significant roles in atherosclerosis. 3,4) Whether telmisartan could be used to treat atherosclerosis with these two roles is unknown.…”

Impact of Angiotensin II Receptor Blockers on the Progression and Regression of Coronary Atherosclerosis An Intravascular Ultrasound Study

“…2 Johnstone et al recently found that ARB (candesartan) in a rabbit model reduced macrophage accumulation, increased collagen deposition within the plaque, reduced the frequency of plaque disruption and thereby attenuated the development of atherosclerosis. 3 ARBs have been reported to decrease macrophage accumulation and chemokine expression, and attenuate LDL oxidation. 31,32 The doses of ARB used in those animal models were far greater than those used in clinical practice, raising doubts about whether the resultant findings can be directly extrapolated to humans.…”

“…[1][2][3][4][5][6] Although Strawn et al found that ARB inhibited fatty-streak formation by protecting low-density lipoprotein (LDL) from oxidation and suppressing vascular monocyte activation in non-human primates, 2 Johnstone et al demonstrated in an animal model that ARB reduce macrophage accumulation and plaque disruption and thereby attenuate the development of atherosclerosis. 3 More recently, 6-month administration of ARB has been reported to reduce the intimal hyperplasia in monkeys with diet-induced hypercholesterolemia.…”