Impaired superoxide production due to a deficiency in phagocyte NADPH oxidase fails to inhibit atherosclerosis in mice

Superoxide, the reduced form of molecular oxygen, has been implicated in th e genesis of vascular disease. One potential mechanism involves oxidation o f low density lipoprotein into an atherogenic particle. A second involves r eaction with nitric oxide to generate peroxynitrite, a highly oxidizing int ermediate. A third involves regulation of signal transduction in artery wal l cells. One well-characterized pathway for superoxide production resides i n macrophages, the cellular hallmark of the early atherosclerotic lesion. M acrophages contain a membrane-bound NADPH oxidase that reduces oxygen to su peroxide. In the current studies, we used mice that are deficient in the gp 91-phox subunit of the NADPH oxidase-a model of chronic granulomatous disea se (CGD)-to explore the role of superoxide in atherosclerotic vascular dise ase. Wild-type and CGD mice on the C57BL/6 background received a high-fat d iet for 20 weeks to induce hypercholesterolemia. At the end of this period, the 2 strains of mice had comparable plasma lipid levels, and their athero sclerotic lesions were similar in size. We also crossed CGD mice with apoli poprotein E-deficient (apoE-/-) mice to generate spontaneously hypercholest erolemic animals that lacked functional NADPH oxidase. After 24 weeks, the CGD-apoE-/- animals had lower plasma cholesterol and triglyceride levels th an did the apoE-/- animals, but there was no difference in the extent of at herosclerotic 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.