on February 13, 2003
Arteriosclerosis, Thrombosis, and Vascular Biology. 2003
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
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Submitted on November 13, 2002
Accepted on December 11, 2002
Increased Superoxide Production in Coronary Arteries in Hyperhomocysteinemia. Role of Tumor Necrosis Factor-
, NAD(P)H Oxidase, and Inducible Nitric Oxide Synthase
Zoltan Ungvari ;
From the Department of Physiology, New York Medical College, Valhalla, NY and Department of Pathophysiology, Semmelweis University, Budapest, Hungary.
* To whom correspondence should be addressed. 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 extracellular nitric oxide synthase, Cu,Zn-SOD, Mn-SOD, ecSOD (mRNA), and xanthine oxidase were 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. TNF- induced a proinflammatory vascular phenotype that potentially contributes to the development of coronary atherosclerosis.
Key words: homocysteine • nonphagocytic NADPH oxidase • cytokine • gene expression
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