Hydrogen peroxide inhibits insulin-induced ATP-sensitive potassium channel activation independent of insulin signaling pathway in cultured vascular smooth muscle cells

Abstract

Both reactive oxygen species (ROS) and insulin resistance have been reported to play essential pathophysiological roles in cardiovascular diseases, such as hypertension and atherosclerosis. However, the mechanistic link between ROS and insulin resistance in the vasculature remains unclear. Recently we have shown that insulin causes membrane hyperpolarization via ATP-sensitive potassium (KATP) channel activation, which is mediated by phosphatidylinositol 3-kinase (PI3-K) in cultured vascular smooth muscle cells (VSMCs). KATP channel in the vasculature is critical in the regulation of vascular tonus. Here we examined the effects of ROS induced by hydrogen peroxide (H2O2) on insulin-induced KATP channel activities in cultured VSMCs, A10 cells. H2O2 (10 μM) increased significantly intercellular ROS in A10 cells. By using a cell-attached patch clamp experiment, 10 μMH2O2 suppressed significantly insulin-induced KATP channel activation without inhibition of insulin receptor signal transduction component including IRS and Akt in A10 cells. Furthermore 10 μMH2O2 suppressed significantly pinacidil-induced KATP channel activation in A10 cells. These data suggest that H2O2might inhibit directly KATP channel independent of insulin signaling pathway. This study may contribute to our understanding of mechanisms of insulin resistance-associated cardiovascular disease.