p22phox-derived superoxide mediates enhanced proliferative capacity of diabetic vascular smooth muscle cells

To investigate the mechanisms that contribute to the acceleration of atherosclerosis in diabetes, the role of NAD(P)H oxidase in the enhanced proliferative capacity of diabetic vascular smooth muscle cells (VSMC) was studied. VSMC from streptozotocin (STZ)-induced diabetic rat aorta had increased proliferative capacity and generated higher levels of superoxide in comparison with cells from control rats. Both the enhanced proliferation and superoxide generation in diabetic VSMC were significantly attenuated not only by tiron (1mM), a superoxide scavenger but also by diphenyleneiodonium (DPI; 10microM), an NAD(P)H oxidase inhibitor. Both the activity of NAD(P)H oxidase and p22phox expression were significantly increased in diabetic VSMC. Furthermore, inhibition of p22phox expression by transfection of antisense p22phox oligonucleotides into diabetic VSMC resulted in a decrease in superoxide generation, which was accompanied by a significant attenuation of cell proliferation. Based on these results, it is suggested that diabetes-associated increase in NAD(P)H oxidase activity via enhanced expression of p22phox contributes to augmented VSMC proliferation in diabetic rats.