Cytochromeb558–Dependent NAD(P)H Oxidase–Phox Units in Smooth Muscle and Macrophages of Atherosclerotic Lesions

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Abstract
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-β1 and interferon-γ. 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.

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