Differential Effect of Hydrogen Peroxide and Superoxide Anion on Apoptosis and Proliferation of Vascular Smooth Muscle Cells

BACKGROUND: Proliferation and apoptosis of vascular smooth muscle cells (VSMCs) are two important components of atherosclerosis, restenosis, and hypertension. Although reactive oxygen species have been demonstrated to participate in the pathogenesis of these diseases, their precise involvement has not been fully understood. We hypothesized that different reactive oxygen species exert distinct effects on proliferation and apoptosis of VSMCs. METHODS AND RESULTS: Cultured rat VSMCs were exposed to xanthine oxidase/xanthine (XO/X) or H2O2-Fe(II). A single exposure to XO/X predominantly resulted in cell proliferation, whereas frequent exposures to high levels of XO/X predominantly resulted in cell death. Administration of superoxide dismutase and catalase revealed that O2- but not H2O2, was mitogenic to VSMCs, whereas H2O2 was responsible for VSMC death. Treatment with H2O2-Fe(II) alone or in the presence of different hydroxyl radical scavengers showed that VSMC death occurred in a dose-dependent manner and was mediated by the formation of hydroxyl radicals. Cell death caused by XO/X or H2O2-Fe(II) occurred by apoptosis as revealed by condensation of nuclei, appearance of a "DNA ladder," increases in DNA fragmentation, and positive in situ nick-end labeling. Northern blot analysis indicated that bcl-2 and c-fos but not p53 and c-myc may participate in mediating H2O2-Fe(II)-induced VSMC apoptosis. CONCLUSIONS: Different reactive oxygen species exert distinct effects on VSMCs, with O2- inducing proliferation and H2O2 causing apoptosis. Thus, reactive oxygen species might participate in atherosclerosis, restenosis, and hypertension in a dual manner by stimulating proliferation and triggering apoptosis of VSMCs.