© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Impaired Superoxide Production Due to a Deficiency in Phagocyte NADPH Oxidase Fails to Inhibit Atherosclerosis in Mice
From the Departments of Pathobiology and Nutritional Sciences (E.A.K., R.C.L.) and Medicine (E.A.K., H.R., A.C., R.C.L.), University of Washington, Seattle; the Departments of Pediatrics and Medical and Molecular Genetics (M.C.D.), Indiana University Medical Center, Indianapolis; and the Departments of Medicine and Molecular Biology and Pharmacology (J.W.H.), Washington University School of Medicine, St. Louis, Mo.
Correspondence to Renée C. LeBoeuf, PhD, Department of Pathobiology, Room 305, Raitt Hall, Box 353410, University of Washington, Seattle, WA 98195. E-mail leboeuf{at}u.washington.edu
Abstract—Superoxide, the reduced form of molecular oxygen, has been implicated in the genesis of vascular disease. One potential mechanism involves oxidation of low density lipoprotein into an atherogenic particle. A second involves reaction with nitric oxide to generate peroxynitrite, a highly oxidizing intermediate. A third involves regulation of signal transduction in artery wall cells. One well-characterized pathway for superoxide production resides in macrophages, the cellular hallmark of the early atherosclerotic lesion. Macrophages contain a membrane-bound NADPH oxidase that reduces oxygen to superoxide. In the current studies, we used mice that are deficient in the gp91-phox subunit of the NADPH oxidase–a model of chronic granulomatous disease (CGD)–to explore the role of superoxide in atherosclerotic vascular disease. Wild-type and CGD mice on the C57BL/6 background received a high-fat diet for 20 weeks to induce hypercholesterolemia. At the end of this period, the 2 strains of mice had comparable plasma lipid levels, and their atherosclerotic lesions were similar in size. We also crossed CGD mice with apolipoprotein E–deficient (apoE-/-) mice to generate spontaneously hypercholesterolemic animals that lacked functional NADPH oxidase. After 24 weeks, the CGD-apoE-/- animals had lower plasma cholesterol and triglyceride levels than did the apoE-/- animals, but there was no difference in the extent of atherosclerotic plaque. Our findings suggest that superoxide generated by the NADPH oxidase of phagocytes does not promote atherosclerosis in mice with either diet-induced or genetic forms of hypercholesterolemia.
Key Words: peroxynitrite • oxidized LDL • lipid peroxidation
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