Circulation. 2002;105:1656-1662
Published online before print March 18, 2002, doi: 10.1161/01.CIR.0000012748.58444.08
Published online before print March 18, 2002, doi: 10.1161/01.CIR.0000012748.58444.08
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(Circulation. 2002;105:1656.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Mechanisms of Increased Vascular Superoxide Production in Human Diabetes Mellitus
Role of NAD(P)H Oxidase and Endothelial Nitric Oxide Synthase
From the Departments of Cardiovascular Medicine (T.J.G., S.M., K.M.C.) and Cardiothoracic Surgery (S.M., D.G., C.R., R.P.), University of Oxford, Oxford, UK, and Departments of Medicine (T.J.G.) and Cardiovascular Surgery and Transplantology (J.S.), Jagiellonian University School of Medicine, Cracow, Poland.
Correspondence to Dr Keith Channon, MD, MRCP, Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail keith.channon{at}cardiov.ox.ac.uk
Background— 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.
Methods and Results— 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.
Conclusions— 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.
Key Words: diabetes mellitus • atherosclerosis • endothelium • superoxide • nitric oxide
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