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Mechanisms of Increased Vascular Superoxide Production in Human Diabetes Mellitus

Tomasz J. GuzikFrom 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, PolandShafi MussaFrom 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, PolandDaniela GastaldiFrom 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, PolandJerzy SadowskiFrom 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, PolandC RatnatungaFrom 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, PolandRavi PillaiFrom 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, PolandKeith M. ChannonFrom 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

2002en

ABI

Annotatsiya

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.

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Identifikatorlar

DOI: 10.1161/01.cir.0000012748.58444.08

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