Role of SIRT1 in vasoprotection

描述（由申请方提供）：氧化应激在衰老期间的血管损伤中起关键作用。本提案的目标是确定新的机制，作为调节血管氧化还原稳态，从而抑制氧化应激诱导的炎症过程中老化。先前的研究表明，热量限制（CR）减弱了与年龄相关的氧化应激增加，并延长了寿命。重要的是，CR的年龄相关效应似乎依赖于NAD+依赖性蛋白脱乙酰酶SIRT 1。SIRT 1在血管系统中表达，并调节多方面的血管保护途径。在拟议的研究中，我们假设CR或SIRT 1的药理学激活剂诱导SIRT 1依赖性通路传递血管保护作用的老化。NF-E2相关因子2（Nrf 2）是一种转录因子，调节许多ROS解毒和抗氧化基因的表达。我们最近已经证明，热量限制通过上调Nrf 2在小鼠中表现出对肿瘤发生的保护作用。我们的初步数据表明，Nrf 2在衰老过程中通过CR发挥类似的血管保护作用。Nrf 2/ARE途径的主要下游效应子是NAD（P）H：醌氧化还原酶（NQO 1）依赖性跨质膜抗氧化剂氧化还原系统。尽管NQO 1被CR上调，但其对内皮细胞氧化应激的保护作用尚不清楚。 拟议项目的总体目标是测试以下假设：热量限制通过激活SIRT 1和诱导Nrf 2调节的ROS解毒系统（包括NQO 1）保护血管系统免受与衰老相关的氧化应激的有害影响。我们认为，内皮细胞中该通路的药理学激活模拟了热量限制的作用，这对衰老过程中血管保护的干预策略有重要贡献。提出了以下目的：1/a：确定热量限制是否通过激活SIRT 1，通过减弱线粒体氧化应激和抑制血管炎症在衰老动物中发挥血管保护作用。1/B：确定SIRT 1药理学激活剂治疗对年龄相关血管损伤的疗效。2/a：确定Nrf 2/ARE通路的诱导是否介导了热量限制在衰老中的血管保护作用。2/B：确定NQO 1依赖性跨质膜抗氧化剂氧化还原系统的上调是否赋予衰老中的血管保护作用。拟议的研究将首次全面分析热量限制有助于预防与年龄相关的血管功能下降的影响和潜在机制。这些实验将提供关于SIRT 1和Nrf 2/ARE途径在生物老化过程中的作用的新的和确定的信息，并将解决与抗氧化系统对心血管功能和年龄相关病理的发生和调节的影响有关的重大争议。

DESCRIPTION (provided by applicant): Oxidative stress plays a key role in vascular impairment during aging. The goal of the present proposal is to identify novel mechanisms that act as regulators of vascular redox homeostasis and thus suppress oxidative stress-induced inflammatory processes in aging. Previous studies indicate that caloric restriction (CR) attenuates the age- related increase in oxidative stress and increases lifespan. Importantly, the age-related effects of CR appear to be dependent on the NAD+ dependent protein deacetylase SIRT1. SIRT1 is expressed in the vasculature and regulates multifaceted vasoprotective pathways. In the proposed studies, we hypothesize that induction of SIRT1- dependent pathways by CR or by pharmacological activators of the enzyme conveys vasoprotective effects in aging. NF-E2-related factor 2 (Nrf2) is a transcription factor, that regulates the expression of numerous ROS detoxifying and antioxidant genes. We have recently demonstrated that caloric restriction exhibits a protective action against tumorigenesis in mice by upregulation of Nrf2. Our preliminary data suggest that Nrf2 plays a similar role in vasoprotection by CR in aging. A major downstream effector of the Nrf2/ARE pathway is the NAD(P)H:quinone oxidoreductase (NQO1) -dependent trans-plasma membrane antioxidant redox system. Although NQO1 is up-regulated by CR, its protection against oxidative stress in endothelial cells is completely unknown. The overall goal of the proposed project is to test the hypothesis that caloric restriction protects the vasculature from the deleterious effects of oxidative stress associated with aging, via activation of SIRT1 and induction of the Nrf2- regulated ROS detoxification systems (including NQO1). We posit that pharmacological activation of this pathway in endothelial cells mimics the effects of caloric restriction, which contributes significantly to an intervention strategy for vasoprotection during aging. The following aims are proposed: 1/a: Determine whether caloric restriction, via activating SIRT1, exerts vasoprotective effects in aging animals by attenuating mitochondrial oxidative stress and inhibiting vascular inflammation. 1/b: Define the efficacy of treatment with pharmacological activators of SIRT1 on age-related vascular impairment. 2/a: Determine whether induction of the Nrf2/ARE pathway mediates the vasoprotective effects of caloric restriction in aging. 2/b: Determine whether up-regulation of the NQO1-dependent trans-plasma membrane antioxidant redox system confers vasoprotection in aging. The proposed studies will provide the first comprehensive analysis on the effects and potential mechanisms through which caloric restriction contributes to preventing the age-related decline in vascular function. These experiments will provide novel and definitive information on the actions of SIRT1 and the Nrf2/ARE pathway during biological aging and will resolve significant controversies related to the effects of antioxidant systems on the genesis and modulation of cardiovascular function and age- related pathology.