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

 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不成比例。糖尿病给退伍军人造成了沉重的损失，使他们的死亡风险翻了一番。大多数糖尿病退伍军人的住院和死亡 是由于血管并发症，如心肌梗死和中风。糖尿病导致这些并发症是因为它促进了血管内皮功能障碍，加速了动脉粥样硬化。氧化应激对血管功能有许多有害影响，是糖尿病血管系统的一个显著特征。P66shc是一种在糖尿病血管中表达的蛋白质，在那里它刺激氧化应激。P66shc是导致糖尿病血管功能障碍和动脉粥样硬化加速的主要因素。P66shc在糖尿病血管中的调节机制尚不清楚。这项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，最终目标是利用这一知识来预防和治疗糖尿病血管疾病。这一应用将探索糖尿病血管内皮细胞中p66shc和SIRTUIN1(SIRT1)赖氨酸脱乙酰酶之间的新关系。它的核心是一个新的假设，即在糖尿病中内皮细胞p66shc是赖氨酸乙酰化的，赖氨酸乙酰化激活了p66shc，即 赖氨酸乙酰化的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，而SIRT1通过直接去乙酰化内皮细胞p66shc来改善糖尿病血管病变。在本申请中提出的研究将询问1)糖尿病赖氨酸乙酰化如何在分子水平激活p66shc，从而促进血管内皮细胞的氧化应激，以及2)如果p66shc不能乙酰化，糖尿病血管功能障碍和疾病是否可以预防或延缓。它将通过使用独特的分子工具来解决这些问题，包括缺乏内皮细胞SIRT1的小鼠和内皮细胞p66shc不可乙酰化的小鼠。为什么要研究SIRT1和p66shc之间的这种新的关系？目前治疗或预防糖尿病血管疾病及其伴随的并发症(包括心脏病发作和中风)的治疗方法严重不足。事实证明，即使是降低血糖在预防糖尿病患者的动脉粥样硬化并发症方面也基本无效。此外，有几种药物已经被开发为SIRT1的激活剂，给人类使用时是安全的。如果这一应用中的研究证明SIRT1通过去乙酰化p66shc在预防糖尿病血管功能障碍和加速动脉粥样硬化方面发挥了重要的有益作用，这些SIRT1激活剂可能会在糖尿病血管疾病的治疗中找到新的用途。此外，显示p66shc的赖氨酸乙酰化是导致糖尿病血管疾病的主要机制，可能为开发将这一乙酰化途径作为治疗糖尿病血管并发症的新疗法的药物打开大门。

 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.