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 demonstra ted to participate in the pathogenesis of these diseases, their precis e involvement has not been fully understood. We hypothesized that diff erent reactive oxygen species exert distinct effects on proliferation and apoptosis of VSMCs. Methods and Results Cultured rat VSMCs were ex posed to xanthine oxidase/xanthine (XO/X) or H2O2-Fe(II). A single exp osure to XO/X predominantly resulted in cell proliferation, whereas fr equent exposures to high levels of XO/X predominantly resulted in cell death. Administration of superoxide dismutase and catalase revealed t hat O-2(-) but not H2O2 was mitogenic to VSMCs, whereas H2O2 was respo nsible for VSMC death. Treatment with H2O2-Fe(II) alone or in the pres ence of different hydroxyl radical scavengers showed that VSMC death o ccurred in a dose-dependent manner and was mediated by the formation o f 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 ni ck-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)-induce d VSMC apoptosis. Conclusions Different reactive oxygen species exert distinct effects on VSMCs, with O-2(-) inducing proliferation and H2O2 causing apoptosis. Thus, reactive oxygen species might participate in atherosclerosis, restenosis, and hypertension in a dual manner by sti mulating proliferation and triggering apoptosis of VSMCs.