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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的 SUMOylation 是一种动态翻译后修饰，涉及 SUMO（小泛素样修饰剂）与靶标的赖氨酸残基缀合影响其功能、定位或稳定性的蛋白质。最近的研究报道 SUMOylation (SUMO2/3) 促进血管内皮功能障碍加速动脉粥样硬化。该应用旨在探索氧化还原依赖性 SUMO2化对脉管系统有害影响的机制，并确定了一个 SUMO2 在血管内皮中的新靶点。我们观察到内皮细胞中 SUMO2 过度表达促进通过主要氧化还原调节因子 p66Shc 抑制氧化应激并损害内皮功能。此外，我们观察到 p66Shc 直接被 SUMO2 在关键的赖氨酸调节 p66Shc 的氧化特性。根据这些证据，我们假设 p66Shc 的 SUMO2 化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。我们已经培育出内皮特异性 SUMO2 转基因小鼠，以及在内皮细胞和整个细胞中表达非 SUMO2 化 p66Shc 的转基因小鼠表达非 SUMO2ylatable p66Shc 的身体敲入小鼠。我们将利用这些小鼠，以及体外操纵 p66Shc SUMO2 化的工具，回答三个问题基本问题：1）SUMO2在内皮细胞中的表达是否促进内皮功能障碍，加速动脉粥样硬化； 2) 是 p66Shc 的 SUMO2 化负责 SUMO2 诱导的内皮功能障碍和动脉粥样硬化；和 3) p66shc 的 SUMO2 化如何促进内皮氧化应激。这些重要问题的答案将确立 SUMO2 作为后损害血管内皮功能并促进的翻译修饰通过 p66Shc 引起动脉粥样硬化。推进这方面的知识可能会导致 SUMO2- 动脉粥样硬化性血管疾病的定向治疗。