Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis - Evidence for involvement of the renin-angiotensin system

Article

关键词: CONVERTING ENZYME-INHIBITION;    CORONARY-ARTERY DISEASE;    BIS-N-METHYLACRIDINIUM;    SMOOTH-MUSCLE CELLS;    ENDOTHELIAL DYSFUNCTION;    ANION PRODUCTION;    LUCIGENIN;    EXPRESSION;    ACTIVATION;    RABBITS;   

DOI  :  10.1161/01.CIR.99.15.2027

来源: SCIE

【 摘 要 】

Background-Angiotensin II activates NAD(P)H-dependent oxidases via AT(1)-receptor stimulation, the most important vascular source of superoxide (O-2.(-)). The AT(1) receptor is upregulated in vitro by low-density lipoprotein. The present study was designed to test whether hypercholesterolemia is associated with increased NAD(P)H-dependent vascular O-2(-) production and whether AT(1)-receptor blockade may inhibit this oxidase and in parallel improve endothelial dysfunction. Methods and Results-Vascular responses were determined by isometric tension studies, and relative rates of vascular O-2.(-) production were determined by use of chemiluminescence with lucigenin, a cypridina luciferin analogue, and electron spin resonance studies. AT(1)-receptor mRNA was quantified by Northern analysis, and AT(1)-receptor density was measured by radioligand binding assays. Hypercholesterolemia was associated with impaired endothelium-dependent vasodilation and increased O-2.(-) production in intact vessels. In vessel homogenates, we found a significant activation of NADH-driven O-2.(-) production in both models of hyperlipidemia. Treatment of cholesterol-fed animals with the AT(1)-receptor antagonist Bay 10-6734 improved endothelial dysfunction, normalized vascular O-2.(-) and NADH-oxidase activity, decreased macrophage infiltration, and reduced early plaque formation. In the setting of hypercholesterolemia, the aortic AT, receptor mRNA was upregulated to 166+/-11%, accompanied by a comparable increase in AT(1)-receptor density. Conclusions-Hypercholesterolemia is associated with AT(1)-receptor upregulation, endothelial dysfunction, and increased NADH-dependent vascular O-2.(-) production. The improvement of endothelial dysfunction, inhibition of the oxidase, and reduction of early plaque formation by an AT(1)-receptor antagonist suggests a crucial role of angiotensin II-mediated O-2.(-) production in the early stage of atherosclerosis.

【 授权许可】

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