SUMO2-p66shc axis in vascular endothelial dysfunction and atherosclerosis

摘要 SUMO化是一种动态的翻译后修饰， SUMO（小泛素样修饰物）与靶标的赖氨酸残基的缀合 影响其功能、定位或稳定性的蛋白质。最近的研究报告说， SUMO化（SUMO 2/3）促进血管内皮功能障碍， 加速动脉粥样硬化本申请旨在探索氧化还原依赖性 SUMO 2化在血管系统中的有害作用的机制，并确定一个 SUMO 2在血管内皮中的新靶点。 我们已经观察到SUMO 2在内皮细胞中的过表达促进了SUMO 2的表达。 氧化应激并通过主氧化还原调节剂p66 Shc损害内皮功能。 此外，我们还观察到p66 Shc在一个关键位点上被SUMO 2直接修饰。 赖氨酸，其调节p66 Shc的氧化性质。根据这些证据，我们 假设p66 Shc SUMO 2化是一个关键的分子机制， 血管氧化应激、内皮功能障碍和动脉粥样硬化。 我们已经产生了内皮特异性SUMO 2转基因小鼠，以及 在内皮细胞中表达非SUMO 2基化p66 Shc的转基因小鼠， 表达非SUMO 2基化p66 Shc的体基因敲入小鼠。我们将利用这些 小鼠，以及在体外操纵p66 Shc的SUMO 2化的工具，以回答三个问题。 基本问题：1）SUMO 2在内皮细胞中的表达是否促进 内皮功能障碍和加速动脉粥样硬化; 2）是p66 Shc的SUMO 2化 负责SUMO 2诱导的内皮功能障碍和动脉粥样硬化;和3） p66 shc的SUMO 2化如何促进内皮细胞氧化应激。 对这些重要问题的回答将确立SUMO 2作为一个后 一种损害血管内皮功能并促进 动脉粥样硬化通过p66 Shc。推进这一知识可能会导致SUMO 2- 动脉粥样硬化性血管疾病的定向治疗。

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.