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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:333.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Coronary Artery Superoxide Production and Nox Isoform Expression in Human Coronary Artery Disease

Tomasz J. Guzik; Jerzy Sadowski; Bartlomiej Guzik; Andrew Jopek; Boguslaw Kapelak; Piotr Przybyowski; Karol Wierzbicki; Ryszard Korbut; David G. Harrison; Keith M. Channon

From the Department of Cardiovascular Medicine (T.J.G., K.M.C.), University of Oxford, John Radcliffe Hospital, United Kingdom; Departments of Medicine, Cardiovascular Surgery, and Transplantology and Pharmacology (T.J.G., J.S., B.G., A.J., B.K., P.P., K.W., R.K.), Jagiellonian University School of Medicine, Krakow, Poland; and the Division of Cardiology (D.G.H., T.J.G.), Emory University, Atlanta, Ga.

Correspondence to Prof Keith M. Channon and Dr Tomasz J Guzik, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail keith.channon{at}cardiov.ox.ac.uk or tguzik@emory.edu

Background— Oxidative stress plays important role in the pathogenesis of atherosclerosis and coronary artery disease (CAD). We aimed to determine the sources and selected molecular mechanisms of oxidative stress in CAD.

Methods and Results— We examined basal and NAD(P)H oxidase-mediated superoxide (O₂·^–) production using lucigenin chemiluminescence, ferricytochrome c and dihydroethidium fluorescence in human coronary arteries from 19 CAD and 17 non-CAD patients undergoing heart transplantation. NAD(P)H oxidase subunits and xanthine oxidase expression were measured. Superoxide production was greater in coronary arteries from patients with CAD, even in vessels without overt atherosclerotic plaques, and was doubled within branching points of coronary arteries. Studies using pharmacological inhibitors and specific substrates showed that NAD(P)H oxidases (60%) and xanthine oxidase (25%) are primary sources of O₂·^– in CAD. Losartan significantly inhibited superoxide production in coronary arteries. NAD(P)H oxidase activity and protein levels of the NADPH oxidase subunits p22phox, p67phox, and p47phox were significantly increased in CAD, as were mRNA levels for p22phox and nox2, and no NAD(P)H oxidase subunit mRNA levels correlated with NAD(P)H oxidase activity in vessels from individual patients. Activity and protein expression of xanthine oxidase were increased in CAD, whereas xanthine dehydrogenase levels were not changed.

Conclusions— Increased expression and activity of NAD(P)H oxidase subunits and xanthine oxidase, in part mediated through angiotensin II and PKC-dependent pathways, are important mechanisms underlying increased oxidative stress in human coronary artery disease.

Vascular oxidative stress is increased in coronary artery disease and in the absence of coronary plaque. It is doubled within vessel branching. NAD(P)H oxidases are the primary sources of O₂·^– and are regulated by protein kinase C and angiotensin II. Oxidase subunit mRNA levels are correlated with vascular NAD(P)H oxidase activity.

Key Words: endothelium • NAD(P)H oxidase • nitric oxide • oxidant stress • reactive oxygen species

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