Mechanisms of Increased Vascular Superoxide Production in Human Diabetes Mellitus

TLDR

Increased superoxide production diminishes vascular nitric‑oxide bioactivity and contributes to endothelial dysfunction in diabetes, while in non‑diabetic vessels endothelial nitric‑oxide synthase scavenges superoxide. The study aimed to characterize the sources and mechanisms of vascular superoxide production in diabetic versus non‑diabetic patients undergoing coronary artery bypass surgery. Superoxide production was quantified in saphenous veins and internal mammary arteries from 45 diabetic and 45 matched non‑diabetic patients. Diabetic vessels exhibited markedly increased NAD(P)H oxidase activity and protein subunits, endothelial nitric‑oxide synthase uncoupling that made the endothelium a net superoxide source (reversible by tetrahydrobiopterin), and protein kinase C inhibition with chelerythrine abrogated the excess superoxide.

Abstract

Increased superoxide production contributes to reduced vascular nitric oxide (NO) bioactivity and endothelial dysfunction in experimental models of diabetes. We characterized the sources and mechanisms underlying vascular superoxide production in human blood vessels from diabetic patients with coronary artery disease compared with nondiabetic patients.Vascular superoxide production was quantified in both saphenous veins and internal mammary arteries from 45 diabetic and 45 matched nondiabetic patients undergoing coronary artery bypass surgery. NAD(P)H-dependent oxidases were important sources of vascular superoxide in both diabetic and nondiabetic patients, but both the activity of this enzyme system and the levels of NAD(P)H oxidase protein subunits (p22phox, p67phox, and p47phox) were significantly increased in diabetic veins and arteries. In nondiabetic vessels, endothelial NO synthase produced NO that scavenged superoxide. However, in diabetic vessels, the endothelium was an additional net source of superoxide production because of dysfunctional endothelial NO synthase that was corrected by intracellular tetrahydrobiopterin supplementation. Furthermore, increased superoxide production in diabetes was abrogated by the protein kinase C inhibitor chelerythrine.These observations suggest important roles for NAD(P)H oxidases, endothelial NO synthase uncoupling, and protein kinase C signaling in mediating increased vascular superoxide production and endothelial dysfunction in human diabetes mellitus.