Role of SIRT1 in vasoprotection

SIRT1 在血管保护中的作用

• 批准号: 8526395
• 负责人: ZOLTAN Istvan UNGVARI
• 金额: $ 35.53万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526395
• 关键词: Age; Age-Months; Age-Years; Aging; American; Animals; Antioxidants; Attenuated; Binding; Biogenesis; Biological Aging; Blood Vessels; Caloric Restriction; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Cell membrane; Cellular Stress Response; Data; Deacetylase; Diet; Distant; Drug Metabolic Detoxication; Elderly; Elements; Endothelial Cells; Endothelium; Enzyme Activators; Enzymes; Exhibits; Free Radicals; Functional disorder; GCLC gene; Gene Expression; Genes; Genetic; Genetic Engineering; Glutathione; Goals; Health; Homeostasis; Impairment; Individual; Inflammation; Inflammatory; Injury; Intervention; Knockout Mice; Liver; Longevity; Mediating; Membrane; Mitochondria; Modeling; Molecular Target; Mouse Strains; Mus; NAD(P)H dehydrogenase (quinone) 1, human; NF-E2-related factor 2; NQO1 gene; Names; Organ; Organism; Oxidation-Reduction; Oxidative Stress; Pathology; Pathway interactions; Play; Process; Proteins; Publications; Resveratrol; Role; Series; System; Testing; Transgenic Mice; Treatment Efficacy; Up-Regulation; Vascular System; Wild Type Mouse; age effect; age related; aged; anti aging; dietary restriction; feeding; improved; mortality; novel; older patient; overexpression; prevent; public health relevance; research study; transcription factor; tumorigenesis; vascular inflammation

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. PUBLIC HEALTH RELEVANCE: Oxidative stress and inflammation plays a central role in the pathophysiology of cardiovascular disease, which is the main cause of mortality among elderly Americans. The goal of this project is to identify novel molecular targets that can be activated pharmacologically to protect the blood vessels from free radical mediated injury and inflammation and thus to improve vascular function in elderly patients. We will test the hypotheses that in the vascular system a protein named SIRT1 mediates multifaceted vasoprotective effects. We posit that treatment with SIRT1-activating molecules, or inducing SIRT-1 by dietary restriction or overexpression of SIRT1 by genetic engineering can exert significant vasoprotective effect in aged mice.

描述（由申请人提供）：氧化应激在衰老过程中的血管损伤中起着关键作用。本提案的目标是确定充当血管氧化还原稳态调节剂的新机制，从而抑制衰老过程中氧化应激诱导的炎症过程。先前的研究表明，热量限制（CR）可以减轻与年龄相关的氧化应激增加并延长寿命。重要的是，CR 与年龄相关的影响似乎依赖于 NAD+ 依赖性蛋白脱乙酰酶 SIRT1。 SIRT1 在脉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，我们假设通过 CR 或酶的药理学激活剂诱导 SIRT1 依赖性途径可在衰老过程中发挥血管保护作用。 NF-E2 相关因子 2 (Nrf2) 是一种转录因子，调节多种 ROS 解毒和抗氧化基因的表达。我们最近证明，热量限制通过上调 Nrf2 对小鼠的肿瘤发生具有保护作用。我们的初步数据表明，Nrf2 在衰老过程中 CR 的血管保护中发挥着类似的作用。 Nrf2/ARE 途径的主要下游效应器是 NAD(P)H:醌氧化还原酶 (NQO1) 依赖性跨质膜抗氧化氧化还原系统。尽管 NQO1 被 CR 上调，但其对内皮细胞氧化应激的保护作用尚不清楚。 该项目的总体目标是检验热量限制通过激活 SIRT1 和诱导 Nrf2 调节的 ROS 解毒系统（包括 NQO1）来保护脉管系统免受与衰老相关的氧化应激的有害影响的假设。我们假设内皮细胞中该通路的药理学激活模拟了热量限制的影响，这对衰老过程中血管保护的干预策略有显着贡献。提出以下目标： 1/a：确定热量限制是否通过激活 SIRT1 通过减弱线粒体氧化应激和抑制血管炎症而对衰老动物发挥血管保护作用。 1/b：定义 SIRT1 药物激活剂治疗年龄相关血管损伤的功效。 2/a：确定 Nrf2/ARE 通路的诱导是否介导衰老过程中热量限制的血管保护作用。 2/b：确定 NQO1 依赖性跨质膜抗氧化氧化还原系统的上调是否在衰老过程中具有血管保护作用。拟议的研究将对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进行首次全面分析。这些实验将为生物衰老过程中 SIRT1 和 Nrf2/ARE 通路的作用提供新颖且明确的信息，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相关的重大争议。 公共卫生相关性：氧化应激和炎症在心血管疾病的病理生理学中发挥着核心作用，心血管疾病是美国老年人死亡的主要原因。该项目的目标是确定可以通过药理学激活的新型分子靶标，以保护血管免受自由基介导的损伤和炎症的影响，从而改善老年患者的血管功能。我们将测试以下假设：在血管系统中，一种名为 SIRT1 的蛋白质介导多方面的血管保护作用。我们认为，用SIRT1激活分子治疗，或通过饮食限制诱导SIRT-1或通过基因工程过度表达SIRT1可以对老年小鼠发挥显着的血管保护作用。