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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2714.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Atherosclerosis Is Attenuated by Limiting Superoxide Generation in Both Macrophages and Vessel Wall Cells

Aleksandr E. Vendrov; Zeenat S. Hakim; Nageswara R. Madamanchi; Mauricio Rojas; Chaitanya Madamanchi; Marschall S. Runge

From the Carolina Cardiovascular Biology Center, Department of Medicine, University of North Carolina, Chapel Hill.

Correspondence to Marschall S. Runge, Department of Medicine, University of North Carolina at Chapel Hill, 3033 Old Clinic Building, Chapel Hill, NC 27599-7005. E-mail mrunge{at}med.unc.edu

Objective— We previously showed that NAD(P)H oxidase deficiency significantly reduces atherosclerosis in apoE^–/– mice. The present study was designed to determine the relative contribution of monocyte/macrophage versus vascular wall cell NAD(P)H oxidase to atherogenesis in this model.

Methods and Results— Cell-specific NAD(P)H oxidase inhibition was achieved via allogenic, sex-mismatched bone marrow transplantation. Aortic atherosclerosis and superoxide production in apoE^–/– mice (Control) with functional NAD(P)H oxidase in both monocytes/macrophages and vascular wall cells was compared with that in apoE^–/– mice with nonfunctional monocyte/macrophage NAD(P)H oxidase (BMO) or nonfunctional vessel wall NAD(P)H oxidase (VWO). A significant decrease in superoxide production and atherosclerotic lesions was observed in BMO and VWO mice compared with control mice. Interestingly, BMO mice had significantly lower plasma oxidized LDL levels compared with control and VWO mice, whereas aortic sections of VWO mice showed decreased expression of cellular adhesion molecules compared with control and BMO mice. NAD(P)H oxidase deficiency also attenuated neointimal hyperplasia and mitogenic protein activation in apoE^–/– mice after arterial injury.

Conclusions— We conclude that (1) both monocyte/macrophages and vessel wall cells play critical roles in atherogenesis; (2) decrease in atherosclerosis results from attenuated superoxide generation in monocyte/macrophages or vessel wall cells; and (3) superoxide generation may impact atherosclerosis, in part, by activating smooth muscle cell mitogenic signaling pathways.

We investigated the relative contribution of monocyte/macrophage versus vascular wall cell NAD(P)H oxidase to atherosclerosis using bone marrow transplantation from apoE^–/–/p47phox^–/– mice to apoE^–/– mice and vice versa. Monocytes/macrophages and vascular wall NAD(P)H oixdases contribute equally to aortic superoxide production and atherosclerosis in apoE^–/– mice.

Key Words: Adhesion molecules • signal transduction • oxidized lipids • reactive oxygen species • thrombin

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