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ORIGINAL RESEARCH ARTICLE

Hydrogen Peroxide Inhibits Insulin Signaling in Vascular Smooth Muscle Cells

Carla D. Gardner^*, Satoru Eguchi, Cherilynn M. Reynolds^*, Kunie Eguchi^*, Gerald D. Frank and Evangeline D. Motley^*,1

^* Department of Anatomy and Physiology, Meharry Medical College, Nashville, Tennessee 37208 and
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Both insulin resistance and reactive oxygen species (ROS) have been reported to play essential pathophysiological roles in cardiovascular diseases, such as hypertension and atherosclerosis. However, the mechanistic link between ROS, such as H₂O₂ and insulin resistance in the vasculature, remains undetermined. Akt, a Ser/Thr kinase, mediates various biological responses induced by insulin. In this study, we examined the effects of H₂O₂ on Akt activation in the insulin-signaling pathway in vascular smooth muscle cells (VSMCs). In VSMCs, insulin stimulates Akt phosphorylation at Ser⁴⁷³. Pretreatment with H₂O₂ concentration- and time-dependently inhibited insulin-induced Akt phosphorylation with significant inhibition observed at 50 µM for 10 min. A ROS inducer, diamide, also inhibited insulin-induced Akt phosphorylation. In addition, H₂O₂ inhibited insulin receptor binding partially and inhibited insulin receptor autophosphorylation almost completely. However, pretreatment with a protein kinase C inhibitor, GF109203X (2 µM), for 30 min did not block the inhibitory effects of H₂O₂ on insulin-induced Akt phosphorylation, suggesting that protein kinase C is not involved in the inhibition by H₂O₂. We conclude that ROS inhibit a critical insulin signal transduction component required for Akt activation in VSMCs, suggesting potential cellular mechanisms of insulin resistance, which would require verification in vivo.

Key Words: hydrogen peroxide • Akt • protein kinase B • insulin resistance • vascular smooth muscle cells

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