Abstract 369: Protein Kinase C Epsilon-dependent Nox Activation Mediates Resistin-induced Cardiovascular Disease

Abstract

Background: Adipokine resistin induces vascular smooth muscle cell (VSMC) dysfunction, implying a vital role in cardiovascular disease. In this study, we examined the in vivo and in vitro effects of resisin and investigated the underlying mechanisms involving protein kinase C epsilon (PKCε) and reactive oxygen species (ROS). Methods: After guide-wire injury of distal left common carotid artery, ApoE-/- mice fed with a western diet were treated with or without subcutaneous infusion of resistin in the presence or absence of PKCε inhibitor for 4 weeks. The progress of intimal hyperplasia was monitored using an ultrasound micro-image system. NADPH oxidase (Nox) activity in the mouse coronary arteries was measured using a chemiluminescence assay. Additionally, we treated human coronary artery smooth muscle with resistin in the presence or absence of PKCε and Nox-specific inhibitors to determine mechanistic and functional effects of resistin in VSMCs functions. Reactive oxygen species (ROS) production was analyzed using confocal microscopy. Results: Resistin significantly enhanced injury-induced intimal hyperplasia in our murine model, which was mitigated by the PKCε inhibitor. Nox activity was also substantially augmented in the injured artery in a resistin-PKCε dependent manner. On the cellular level, resistin-induced ROS production was time-dependent and mitochondrial ROS seemed to be the trigger for cytosolic Nox-induced ROS. Inhibition of Nox completely abolished resistin-exaggerated VSMC proliferation, migration and dedifferentiation. Consistently, inhibition of PKCε significantly reduced resistin-induced cytosolic ROS production, Nox activity, and VSMC dysfunction. Conclusion: This is the first study showing that resistin-induced VSMC dysfunction and intimal hyperplasia is mediated through PKCε-dependent Nox activation pathway. These findings suggest potential molecular targets for cardiovascular disease.