Dose-dependent regulation of NAD(P)H oxidase expression b angiotensin II in human endothelial cells - Protective effect of angiotensin II type 1 receptor blockade in patients with coronary artery disease

Objective-Angiotensin II (Ang II)-mediated induction of vascular superoxide anion formation could contribute to the development of endothelial dysfunction, hypertension, and atherosclerosis. An NAD(P)H oxidase has been identified as a major endothelial source of superoxide anions. However, the molecular mechanism underlying the regulation of NAD(P)H oxidase activity in response to Ang 11 is not well understood. Methods and Results-We investigated the dose-dependent regulation of superoxide anion formation and of NAD(P)H oxidase subunit expression in response to Ang 11 in human endothelial cells, Ang 11 regulates superoxide anion formation and the limiting subunit of endothelial NAD(P)H oxidase, gp91-phox, in a dose-dependent manner via Ang 11 type I (AT,) receptor-mediated induction and Ang 11 type 2 receptor-mediated partial inhibition at higher Ang 11 concentrations. Furthermore, AT, receptor blocker therapy before coronary bypass surgery downregulates the gp91-phox expression in internal mammary artery biopsies of patients with coronary artery disease. Conclusions-Our data support a dose-dependent induction of proatherosclerotic oxidative stress in human endothelial cells in response to Ang II. The expression of NAD(P)H oxidase subunit gp91-phox is critical for endothelial superoxide anion formation. AT, receptor blockade has an antiatherosclerotic and antioxidative potential by the reduction of oxidative stress in the vessel wall.