Attenuation of Tissue P-Selectin and MCP-1 Expression and Intimal Proliferation by AT1 Receptor Blockade in Hyperlipidemic Rabbits

Abstract

Angiotensin-II (Ang-II) participates in the development and progression of atherosclerosis by activating type 1 (AT1) receptors. In vitro studies show that inflammatory factors, such as P-selectin and MCP-1, which can be upregulated by Ang-II, play an important role in atherogenesis. We examined the effect of AT1 receptor blockade with losartan on the expression of P-selectin and MCP-1 in hypercholesterolemic rabbits. Since AT1 receptor blockade is associated with feedback upregulation of renin-angiotensin system (RAS), we also examined alterations in plasma Ang-II levels by losartan therapy. Male NZW rabbits were fed regular chow (high cholesterol diet or high cholesterol diet + losartan 25 mg/kg/day). As expected, there was a marked intimal proliferation in association with increase in serum cholesterol (P < 0.001). In addition, there was a modest increase in plasma Ang-II levels (P < 0.05), and a significant increase in the expression of AT1 receptors, P-selectin and MCP-1 in aortas of high cholesterol diet rabbits. Concurrent administration of losartan with high cholesterol diet attenuated aortic intimal proliferation induced a fivefold increase in plasma Ang-II levels and caused a marked decrease in expression of P-selectin and MCP-1 without change in serum lipid levels and aortic AT1 receptor expression. These observations in hypercholesterolemic animal models show that AT1 receptor blockade is associated with modulation of P-selectin and MCP-1 expression concurrent with reduction in intimal proliferation. The rise in plasma Ang-II does not appear to limit the potential beneficial effect of losartan.