SUMO2-p66shc axis in vascular endothelial dysfunction and atherosclerosis

SUMO2-p66shc 轴在血管内皮功能障碍和动脉粥样硬化中的作用

• 批准号: 10363680
• 负责人: Santosh Kumar
• 金额: $ 41.5万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363680
• 关键词: Affect; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Biological Assay; Biological Availability; Blood Vessels; Breeding; Cells; Cessation of life; DNA Modification Process; Data; Deposition; Development; Disease; Endothelial Cells; Endothelium; Experimental Animal Model; Fatty acid glycerol esters; Health; Heat-Shock Proteins 70; Hyperlipidemia; ICAM1 gene; Impairment; In Vitro; Knock-in Mouse; Knock-out; Knowledge; Lead; Low-Density Lipoproteins; Lysine; Measures; Mitochondria; Molecular; Mus; Myocardial Infarction; Myocardial Ischemia; Nitric Oxide; Organ; Outcome; Oxidation-Reduction; Oxidative Stress; Paralysed; Phosphorylation; Physiological; Post-Translational Protein Processing; Production; Property; Proteins; Reactive Oxygen Species; Reporting; Risk Factors; Role; Stroke; Sumoylation Pathway; Testing; Transgenic Mice; Transgenic Organisms; Ubiquitin; Vascular Diseases; Vascular Endothelium; Vascular blood supply; Vasodilation; base; endothelial dysfunction; inflammatory marker; novel; novel therapeutic intervention; overexpression; p66(ShcA) protein; sensor; tool; vascular endothelial dysfunction; vascular inflammation

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.

抽象的 sumoylation是一种动态的翻译后修饰，涉及 Sumos（小型泛素样修饰剂）与赖氨酸残基的共轭剂量/s 影响其功能，定位或稳定性的蛋白质。最近的研究报道了 Sumoylation（SUMO2/3）促进了血管内皮功能障碍和 加速动脉粥样硬化。该应用程序旨在探索依赖氧化还原的 Sumo2ylation在脉管系统中的有害作用的机制，并确定 SUMO2在血管内皮中的新靶标。 我们观察到内皮细胞中的SUMO2过表达促进 氧化应激和通过主氧化还原调节剂p66SHC损害内皮功能。 此外，我们已经观察到p66SHC是由sumo2直接修改的 调节P66SHC的氧化特性的赖氨酸。基于这些证据，我们 假设p66SHC的sumo2ylation是驱动的关键分子机制 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SUMO2转基因小鼠，以及 在内皮中表达不舒张2ylabable P66SHC的转基因小鼠，整个 表达不可用的P66SHC的人体敲击小鼠。我们将利用这些 小鼠以及在体外操纵p66SHC的Sumo2ylation的工具，以回答三个 基本问题：1）在内皮中sumo2表达促进 内皮功能障碍和加速动脉粥样硬化； 2）是p66SHC的sumo2ylation 负责SUMO2诱导的内皮功能障碍和动脉粥样硬化； 3） p66SHC的SUMO2yl化如何促进内皮氧化应激。 这些重要问题的答案将确定sumo2作为后的作用 - 翻译修饰会损害血管内皮功能并促进 动脉粥样硬化通过P66SHC。促进这些知识可能会导致sumo2- 针对动脉粥样硬化血管疾病的定向疗法。