Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:418-424
Published online before print February 13, 2003, doi: 10.1161/01.ATV.0000061735.85377.40
Published online before print February 13, 2003, doi: 10.1161/01.ATV.0000061735.85377.40
© 2003 American Heart Association, Inc.
Vascular Biology |
Increased Superoxide Production in Coronary Arteries in Hyperhomocysteinemia
Role of Tumor Necrosis Factor-
, NAD(P)H Oxidase, and Inducible Nitric Oxide Synthase
From the Department of Physiology (Z.U., A.C., J.G.E., P.M.K., M.S.W., G.K., A.K.), New York Medical College, Valhalla, NY and Department of Pathophysiology (Z.U., A.C., A.K.), Semmelweis University, Budapest, Hungary.
Correspondence to Akos Koller MD, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail koller{at}nymc.edu
Objective— In coronary arteries, hyperhomocysteinemia (HHcy, a known risk factor for coronary heart disease) impairs flow-induced dilations, which can be reversed by superoxide dismutase (SOD). To evidence increased O2.- generation and elucidate its source, we characterized changes in activity (lucigenin chemiluminescence, hydroethidine staining) and expression of arterial pro- and antioxidant systems (Western blotting, immunohistochemistry, cDNA microarray, reverse-transcription polymerase chain reaction) in the coronary arteries of rats by using methionine diet-induced HHcy.
Methods and Results— The increased generation of O2.- by HHcy coronary arteries was inhibited by SOD, diphenyleneiodonium, apocynin, and apocynin plus amino guanidine but was unaffected by allopurinol and rotenone. Also, diphenyleneiodonium-sensitive NADPH-driven O2.- generation was increased in HHcy vessels. In HHcy arteries expression of the smooth muscle-confined NAD(P)H oxidase subunit nox1 and that of iNOS was increased. Expression of p67phox, p22phox, and p47phox subunits and that of endothelial nitric oxide synthase, Cu,Zn-SOD, Mn-SOD, extracellular SOD (mRNA), and xanthine oxidase was unchanged. Microarray analysis showed increased expression of tumor necrosis factor (TNF)- (confirmed by reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemistry) that was localized in smooth muscle. In vitro incubation (18 hours) of HHcy arteries with anti-TNF- antibody decreased O2.- production, whereas incubation of control vessels with TNF- increased O2.- generation and nox1 expression.
Conclusions— In coronary arteries, HHcy increases TNF- expression, which enhances oxidative stress through upregulating a nox1-based NAD(P)H oxidase and inducible nitric oxide synthase. Thus, TNF- induces a proinflammatory vascular phenotype in HHcy that potentially contributes to the development of coronary atherosclerosis.
Key Words: homocysteine • nonphagocytic NADPH oxidase • cytokine • gene expression
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