['Resistin has been implicated in cardiovascular disease and poor interventional cardiovascular outcomes. Previous studies by our group demonstrated resistin promoted vascular smooth muscle cell (VSMC) migration through protein kinase C epsilon (PKCε) pathways, while few others showed that resistin induced reactive oxygen species (ROS) generation in various cell types. In this study, we aim to systemically examine the functional role of resistin at the cellular and tissue levels as well as the potential mechanistic relationship between resistin-induced PKCε activation and ROS production.', 'Plasma collected from patients undergoing carotid interventions was analyzed for resistin level and ROS. VSMCs were treated with resistin in the presence or absence of PKCε and NADPH oxidase (Nox)-specific inhibitors. Intracellular ROS production was analyzed using confocal microscopy and Nox activity with chemiluminescence. In\xa0vivo studies were performed in apolipoprotein E knock out (ApoE', 'We observed significant correlation between plasma resistin and circulating levels of oxidative stress in patients with severe atherosclerotic disease. We also demonstrated that resistin induced ROS production via PKCε-mediated Nox activation. Resistin-induced ROS production was time-dependent, and Nox4 was the primary isoform involved. Inhibition of Nox completely abolished resistin-exaggerated VSMC proliferation, migration and dedifferentiation, as well as pro-inflammatory cytokine release. Upstream modulation of PKCε significantly reduced resistin-mediated cytosolic ROS, Nox activity and VSMC dysfunction. Moreover, PKCε-specific inhibitor mitigated resistin-induced Nox activation and intimal hyperplasia in ApoE'] Does pKCε mediate resistin-induced NADPH oxidase activation and inflammation leading to smooth muscle cell dysfunction and intimal hyperplasia?