SIRTUIN1-mediated inhibition of p66shc lysine acetylation as a novel treatment for diabetic vasculopathy

SIRTUIN1 介导的 p66shc 赖氨酸乙酰化抑制作为糖尿病血管病变的新型治疗方法

• 批准号: 9135028
• 负责人: Kaikobad J. Irani
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135028
• 关键词: Acetylation; Address; Atherosclerosis; Attention; Binding; Blood Glucose; Blood Vessels; Cessation of life; Cholesterol; Complications of Diabetes Mellitus; Cytochromes; Deacetylase; Development; Diabetes Mellitus; Diabetic Angiopathies; Diagnosis; Disease; Dominant-Negative Mutation; Down-Regulation; Endothelium; Enzymes; FOXO3A gene; Family; Figs - dietary; Functional disorder; General Population; Goals; Health Benefit; Health system; Hospitalization; Human; Knock-in Mouse; Knowledge; Lead; Lysine; Mediating; Mitochondria; Molecular; Mus; Myocardial Infarction; NADPH Oxidase; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Pathway interactions; Pharmacologic Substance; Phosphorylation; Play; Population; Proteins; Public Health; Reactive Oxygen Species; Recruitment Activity; Risk; Role; Serine; Stroke; Testing; Transgenic Mice; Vascular Diseases; Vascular Endothelium; Vasodilation; Veterans; antioxidant enzyme; clinically relevant; design; diabetic; endothelial dysfunction; member; mitochondrial permeability transition pore; mortality; novel; novel therapeutics; p66(ShcA) protein; prevent; protein function; public health relevance; therapeutic target; tool; vascular endothelial dysfunction; vasculogenesis

 DESCRIPTION (provided by applicant): Diabetes is a worldwide public health problem. Veterans are disproportionally impacted by diabetes compared to the general population. Diabetes exacts a heavy toll on veterans, doubling their risk of death. The majority of hospitalizations and deaths in veterans with diabetes are due to vascular complications such as myocardial infarctions and strokes. Diabetes leads to these complications because it promotes dysfunction of the vascular endothelium and accelerates atherosclerosis. Oxidative stress has many deleterious effects on blood vessel function and is a prominent feature of the diabetic vasculature. P66shc is a protein expressed in diabetic blood vessels where it stimulates oxidative stress. P66shc is a major factor responsible for diabetic vascular dysfunction and accelerated atherosclerosis. How p66shc is regulated in diabetic blood vessels is not known. The immediate goal of this application is to understand the fundamental mechanism governing p66shc function in diabetic blood vessels, with the eventual goal of leveraging this knowledge to prevent and treat diabetic vascular disease. This application will explore a novel relationship between p66shc and the SIRTUIN1 (SIRT1) lysine deacetylase in the diabetic vascular endothelium. It centers on the novel hypothesis that endothelial p66shc is lysine acetylated in diabetes, that lysine acetylation activates p66shc, that lysine acetylated p66shc plays an indispensable role in leading to diabetic vascular dysfunction and accelerated atherosclerosis, and SIRT1 ameliorates diabetic vascular disease by directly deacetylating endothelial p66shc. Studies proposed in this application will ask 1) how lysine acetylation by diabetes activates p66shc at the molecular level, thus promoting oxidative stress in the vascular endothelium, and 2) whether diabetic vascular dysfunction and disease can be prevented or retarded if p66shc cannot be acetylated. It will address these points by using unique molecular tools including mice lacking endothelial SIRT1 and mice in which endothelial p66shc is not acetylatable. Why investigate this novel relationship between SIRT1 and p66shc? Current therapies to treat or prevent diabetic vascular disease and its attendant complications, including heart attacks and strokes, are woefully inadequate. Even reducing blood sugar has proven largely ineffective in preventing atherosclerotic complications of diabetics. Add to this that there are several pharmaceuticals that have been developed as activators of SIRT1 and are safe when given to humans. If studies in this application prove that SIRT1 plays a major beneficial role in preventing vascular dysfunction and accelerated atherosclerosis of diabetes by deacetylating p66shc, these SIRT1 activators could find a new use in the treatment of diabetic vascular disease. In addition, showing that lysine acetylation of p66shc is the principal mechanism responsible for diabetic vascular disease could open the door for developing pharmaceuticals that target this acetylation pathway as novel therapies for diabetic vascular complications.

 描述（由申请人提供）： 糖尿病是一个世界性的公共卫生问题。与普通人群相比，退伍军人受到糖尿病的影响尤为严重。糖尿病给退伍军人带来了沉重的负担，使他们的死亡风险增加了一倍。大多数住院和死亡的退伍军人患有糖尿病 是由于心肌梗塞和中风等血管并发症引起的。糖尿病会导致这些并发症，因为它会促进血管内皮功能障碍并加速动脉粥样硬化。 氧化应激对血管功能有许多有害影响，并且是糖尿病脉管系统的一个显着特征。 P66shc 是一种在糖尿病血管中表达的蛋白质，可刺激氧化应激。 P66shc 是导致糖尿病血管功能障碍和加速动脉粥样硬化的主要因素。 p66shc 在糖尿病血管中的调节机制尚不清楚。该应用的直接目标是了解控制糖尿病血管中 p66shc 功能的基本机制，最终目标是利用这些知识来预防和治疗糖尿病血管疾病。 该应用将探索糖尿病血管内皮细胞中 p66shc 与 SIRTUIN1 (SIRT1) 赖氨酸脱乙酰酶之间的新关系。它以一个新的假设为中心，即糖尿病中内皮 p66shc 被赖氨酸乙酰化，赖氨酸乙酰化激活 p66shc， 赖氨酸乙酰化p66shc在导致糖尿病血管功能障碍和加速动脉粥样硬化中起着不可或缺的作用，SIRT1通过直接使内皮p66shc去乙酰化来改善糖尿病血管疾病。本申请中提出的研究将提出以下问题：1) 糖尿病引起的赖氨酸乙酰化如何在分子水平上激活 p66shc，从而促进血管内皮的氧化应激；2) 如果 p66shc 不能乙酰化，是否可以预防或延缓糖尿病血管功能障碍和疾病。它将通过使用独特的分子工具来解决这些问题，包括缺乏内皮 SIRT1 的小鼠和内皮 p66shc 不可乙酰化的小鼠。 为什么要研究 SIRT1 和 p66shc 之间的这种新颖关系？目前治疗或预防糖尿病血管疾病及其伴随并发症（包括心脏病和中风）的疗法严重不足。事实证明，即使降低血糖对于预防糖尿病患者的动脉粥样硬化并发症也基本上无效。除此之外，有几种药物已被开发为 SIRT1 激活剂，并且给予人类时是安全的。如果本申请中的研究证明 SIRT1 通过 p66shc 去乙酰化在预防血管功能障碍和加速糖尿病动脉粥样硬化方面发挥重要的有益作用，那么这些 SIRT1 激活剂可以在治疗糖尿病血管疾病中找到新用途。此外，表明p66shc的赖氨酸乙酰化是导致糖尿病血管疾病的主要机制，这可能为开发针对该乙酰化途径的药物作为糖尿病血管并发症的新疗法打开大门。