Attenuation of tissue P-selectin and MCP-1 expression and intimal proliferation by AT(1) receptor blockade in hyperlipidemic rabbits

Angiotensin-II (Ang-II) participates in the development and progression of atherosclerosis by activating type 1 (AT(1)) receptors. In vitro studies sh ow that inflammatory factors, such as P-selectin and MCP-1, which can be up regulated by Ang-II, play an important role in atherogenesis, We examined t he effect of AT(1) receptor blockade with losartan on the expression of P-s electin and MCP-1 in hypercholesterolemic rabbits. Since AT(1) receptor blo ckade is associated with feedback upregulation of renin-angiotensin system (RAS), we also examined alterations in plasma Ang-II levels by losartan the rapy. 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 AT(1) receptor s, P-selectin and MCP-1 in aortas of high cholesterol diet rabbits. Concurr ent 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 AT(1) receptor expression. These ob servations in hypercholesterolemic animal models show that AT(1) receptor b lockade is associated with modulation of P-selectin and MCP-1 expression co ncurrent with reduction in intimal proliferation. The rise in plasma Ang-II does not appear to limit the potential beneficial effect of losartan. (C) 2001 Academic Press.