Systemic Regulation of Vascular NAD(P)H Oxidase Activity and Nox Isoform Expression in Human Arteries and Veins

Abstract

Objective-Impaired endothelial function, characterized by nitric oxide scavenging by increased superoxide production, is a hallmark of vascular disease states. However, molecular mechanisms regulating superoxide production in human blood vessels remain poorly defined. Methods and Results-We compared endothelial function, vascular superoxide production, and the expression of NAD(P)H oxidase subunits in arteries and veins from patients undergoing coronary bypass surgery (nϭ86). Superoxide release was similar in arteries and veins. Inhibitor studies revealed that the NAD(P)H oxidase system was a quantitatively and proportionately greater source of superoxide in veins, whereas xanthine oxidase also contributed significantly to superoxide production in arteries. Moreover, NAD(P)H oxidase molecular composition differed in veins and arteries; veins expressed more nox2 and p22phox, whereas the relative expression of nox4 was greater in arteries. However, there were strong correlations between p22phox and nox4 expression and between superoxide production, NAD(P)H oxidase activity, and endothelial function in arteries and veins from the same patient. Conclusions-In individuals with coronary artery disease, changes in vascular superoxide production, endothelial function, and NAD(P)H oxidase activity and expression are related in veins and arteries. These findings highlight the importance of systemic effects on the molecular regulation of the NAD(P)H oxidases in human vascular disease. Key Words: endothelium Ⅲ oxidant stress Ⅲ reactive oxygen species Ⅲ nitric oxide Ⅲ NAD(P)H oxidase O xidative stress plays an important role in the pathogenesis of atherosclerosis, hypertension, and other vascular diseases. In particular, overproduction of superoxide anion may be detrimental because of its rapid interaction with nitric oxide (NO), which leads to the loss of NO bioavailability and reduces its anti-atherogenic effects. 1 Superoxide also regulates redoxsensitive signaling pathways, acts as a direct vascular smooth muscle cell (VSMC) mitogen, and modulates vessel remodeling and plaque stability. 1 Recent studies indicate that patients with endothelial dysfunction in whom arterial superoxide production is increased are at highest risk for vascular morbidity and mortality. 2 The sources of vascular superoxide include NAD(P)H oxidases, xanthine oxidase, cyclooxygenases, nitric oxide synthases, or mitochondrial oxidases. 1,3,4 In particular, NAD(P)H oxidases have been identified as a major enzyme system involved in the generation of vascular oxidative stress. 5 Recent studies have revealed several molecular homologs of the NAD(P)H oxidase large subunit (termed nox-nonphagocytic oxidase). The molecular composition of vascular NAD(P)H oxidases appears to vary in different cell types and at different stages of atherosclerotic plaques. 3 However, the molecular regulation of the NAD(P)H oxidases within atherosclerotic plaques may be more relevant to plaque events, such as rupture, rather than reflecting systemic changes related to global ...

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