Inhibition of early atherogenesis by losartan in monkeys with diet-inducedhypercholesterolemia

Background-Angiotensin II may contribute to atherogenesis by facilitating t he proliferative and inflammatory response to hypercholesterolemia. This st udy determined, in a primate model of diet-induced atherosclerosis, the eff ect of AT(1) blockade on fatty-streak formation, plasma lipids, and surroga te markers of vascular injury. Methods and Results-Male cynomolgus monkeys fed a diet containing 0.067 mg cholesterol/kJ for 20 weeks were given losartan (180 mg/d, n=6) or vehicle (n=8) for 6 weeks starting at week 12 of the dietary regimen. Arterial pres sure, heart rate, plasma total and lipoprotein cholesterol concentrations, and lipoprotein particle sizes and subclass distributions were unaffected b y treatment. Losartan caused significant (P<0.05) increases in plasma angio tensin II and angiotensin-(1-7). Compared with vehicle-treated controls, lo sartan reduced the extent of fatty streak in the aorta, the coronary arteri es, and the carotid arteries by approximate to 50% (P<0.05). A significant (P<0.05) reduction in the susceptibility of LDL to in vitro oxidation, seru m levels of monocyte chemoattractant protein-1, and circulating monocyte CD 11b expression were also associated with losartan treatment. In addition, s erum levels of vascular cell adhesion molecule-1 and E-selectin did not cha nge during treatment but increased after discontinuation of losartan. Serum C-reactive protein, platelet aggregability, and white cell counts were not modified by losartan. Conclusions-This study demonstrates for the first time an antiatherogenic e ffect of AT(1) receptor blockade in nonhuman primates. Losartan inhibited f atty-streak formation through mechanisms that may include protection of LDL From oxidation and suppression of vascular monocyte activation and recruit ment factors.