on October 3, 2002
Published online before print October 3, 2002, doi: 10.1161/01.ATV.0000040222.02255.0F
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Submitted on August 1, 2002
Accepted on September 10, 2002
Cytochrome b558-Dependent NAD(P)H Oxidase-Phox Units in Smooth Muscle and Macrophages of Atherosclerotic Lesions
Natalia Kalinina *;
From the Baker Medical Research Institute (N.K., A.A., P.K., A.B.), Alfred Hospital, Melbourne, Australia; the Institute of Experimental Cardiology (N.K., E.T., Y.A., O.I., V.S.), Cardiology Research Center, Moscow, Russia; and the Department of Veterinary Molecular Biology (M.T.Q.), Montana State University, Bozeman.
* To whom correspondence should be addressed. E-mail: cardiocell{at}cardio.ru.
Objective—Despite studies implicating superoxide anion-producing oxidases in atherosclerosis, their characteristics, expression, and regulation in cells of lesions are poorly understood. We examined the following: (1) whether cytochrome b558-dependent NAD(P)H oxidase-phox peptides are expressed by intimal smooth muscle cells (iSMCs) and macrophages of human aortic atherosclerotic lesions and their regulation and (2) whether cytochrome b558-dependent NAD(P)H oxidase represents a major NAD(P)H oxidase in iSMCs.
Methods and Results—Using a combination of immunochemical and reverse transcription-polymerase chain reaction procedures, we demonstrate that p22phox and gp91phox (cytochrome b558) expression in normal intima was restricted to a quarter of the iSMCs. In fatty streaks, a similar fraction of iSMCs expressed cytochrome b558, whereas macrophages also expressed low levels of p47phox and p67phox. In fibrofatty lesions, the majority of iSMCs expressed the cytochrome b558 subunits; p67phox was also detected. Macrophages and macrophage-derived foam cells expressed the 4 phox subunits that constitute superoxide-producing cytochrome b558-dependent NAD(P)H oxidase. These were upregulated by transforming growth factor-ß1 and interferon-
. Aortic lesions also expressed Thox1 and Nox4, and although their expression also increases with lesion severity, their expression is less frequent than that of gp91phox.
Conclusions—In human aortic fibrofatty lesions, a cytochrome b558-dependent NAD(P)H oxidase appears to be a major iSMC and macrophage oxidase whose expression is upregulated by cytokines.
Key words: atherosclerosis • gp91phox • Thox1 • Nox4 • cytokines
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