Low-density lipoprotein reduction by simvastatin is accompanied by angiotensin II type 1 receptor downregulation, reduced oxidative stress, and improved endothelial function in patients with stable coronary artery disease.

OBJECTIVES: We tested the hypothesis that low-density lipoprotein-cholesterol induces angiotensin II type 1 receptor upregulation that, in turn, accounts for enhanced oxidative stress, and the subsequent endothelial dysfunction in patients with coronary artery disease. METHODS: Brachial artery flow-mediated vasodilation, serum 8-iso-prostaglandin F2alpha (8-isoprostane), and angiotensin II type 1 receptor density on platelets were measured in 19 patients with coronary artery disease, at entry and after 12 weeks of simvastatin therapy, 40 mg/day. RESULTS: At entry there was a significant linear correlation between: angiotensin II type 1 receptor density and plasma low-density lipoprotein-cholesterol; plasma 8-isoprostane and angiotensin II type 1 receptor density; and flow-mediated vasodilation and 8-isoprostane. Simvastatin therapy reduced low-density lipoprotein-cholesterol, downregulated angiotensin II type 1 receptor, decreased 8-isoprostane, and improved flow-mediated vasodilation. The slopes of the presimvastatin and the postsimvastatin angiotensin II type 1 receptor/low-density lipoprotein relationships did not significantly differ, indicating that simvastatin caused a downregulation of angiotensin II type 1 receptor that could be predicted by the low-density lipoprotein reduction. In addition, simvastatin-mediated changes in 8-isoprostane could be predicted by angiotensin II type 1 receptor downregulation, and flow-mediated vasodilation improvement by changes in 8-isoprostane. A significant correlation existed between simvastatin-mediated changes in 8-isoprostane and angiotensin II type 1 receptor. CONCLUSION: The results of this study are consistent with the hypothesis that in coronary artery disease, the impairment of endothelial function is strongly associated with oxidative stress, oxidative stress with cellular angiotensin II type 1 receptor density, and the angiotensin II type 1 receptor density with low-density lipoprotein-cholesterol, suggesting cause-effect relationships between these variables. In support for this notion, these baseline associations were not significantly disturbed by low-density lipoprotein-lowering therapy with simvastatin.