SUMO2-p66shc axis in vascular endothelial dysfunction and atherosclerosis

点击翻译按钮获取中文摘要

ABSTRACT SUMOylation is a dynamic post-translational modification which involves the conjugation of SUMOs (Small Ubiquitin-Like Modifiers) to the lysine residue/s of target proteins affecting their function, localization or stability. Recent studies have reported that SUMOylation (SUMO2/3) promotes vascular endothelial dysfunction and accelerates atherosclerosis. This application aims to explore a redox-dependent mechanism for the deleterious effect of SUMO2ylation in the vasculature, and identify a novel target of SUMO2 in the vascular endothelium. We have observed that SUMO2 overexpression in endothelial cells promotes oxidative stress and impairs endothelial function via the master redox regulator p66Shc. Furthermore, we have observed that p66Shc is directly modified by SUMO2 on a critical lysine that regulates the oxidative property of p66Shc. Based on this evidence, we hypothesize that SUMO2ylation of p66Shc is a key molecular mechanism driving vascular oxidative stress, endothelial dysfunction, and atherosclerosis. We have generated endothelium-specific SUMO2 transgenic mice, as well as transgenic mice expressing non-SUMO2ylatable p66Shc in the endothelium, and whole body knockin mice expressing non-SUMO2ylatable p66Shc. We will leverage these mice, as well as tools to manipulate SUMO2ylation of p66Shc in vitro, to answer three fundamental questions: 1) does SUMO2 expression in the endothelium promote endothelial dysfunction and accelerate atherosclerosis; 2) is SUMO2ylation of p66Shc responsible for SUMO2-induced endothelial dysfunction and atherosclerosis; and 3) how does SUMO2ylation of p66shc promote endothelial oxidative stress. Answers to these important questions will establish the role of SUMO2 as a post- translational modification that impairs vascular endothelial function and promotes atherosclerosis via p66Shc. Advancing this knowledge could potentially lead to SUMO2- directed therapies for atherosclerotic vascular disease.