Role of SIRT1 in vasoprotection

SIRT1 在血管保护中的作用

基本信息

批准号：
8131832
负责人：
ZOLTAN Istvan UNGVARI
金额：
$ 36.63万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
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/8131832
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

项目摘要

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）：氧化应激在老化期间血管损伤中起关键作用。本提案的目的是确定充当血管氧化还原稳态调节剂的新型机制，从而抑制衰老中氧化应激诱导的炎症过程。先前的研究表明，热量限制（CR）减弱了氧化应激与年龄相关的增加并增加了寿命。重要的是，CR的年龄相关作用似乎取决于NAD+依赖性蛋白脱乙酰基酶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CR或酶的药理学激活剂诱导SIRT1依赖性途径，传达了衰老中的血管保护作用。 NF-E2相关因子2（NRF2）是转录因子，它调节了许多ROS排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表现出针对小鼠肿瘤发生的保护作用。我们的初步数据表明，NRF2在CR在衰老中的血管保护中起着相似的作用。 NRF2/是途径的主要下游效应子是NAD（p）H：喹酮氧化还原酶（NQO1）依赖性的反倍于plasmammmbrane抗氧化剂氧化还原氧化还原系统。尽管NQO1被CR上调，但其对内皮细胞中氧化应激的保护是完全未知的。拟议项目的总体目标是检验以下假设：热量限制可以保护脉管系统免受与衰老相关的氧化应激的有害作用，通过激活SIRT1和诱导NRF2-调节的ROS ROS排毒系统（包括NQO1）。我们认为，内皮细胞中该途径的药理激活模仿了热量限制的影响，这在衰老过程中对干预策略产生了显着贡献。提出了以下目的：1/a：通过激活SIRT1通过减弱线粒体氧化应激和抑制血管炎症来确定卡路里限制是否通过激活SIRT1来对衰老动物产生血管保护作用。 1/b：定义SIRT1药理学激活剂治疗对年龄相关血管损伤的功效。 2/A：确定NRF2/是途径的诱导是否介导了衰老中热量限制的血管保护作用。 2/b：确定NQO1依赖性的跨质膜抗氧化剂氧化还原系统的上调是否在衰老中赋予了血管保护。拟议的研究将对热量限制有助于防止与年龄相关的血管功能下降的影响和潜在机制进行首次综合分析。这些实验将提供有关SIRT1和NRF2/是生物衰老过程中的途径的新颖和确定的信息，并将解决与抗氧化剂系统对心血管功能的起源和调制相关的影响的重大争议。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起着核心作用，这是老年美国人死亡的主要原因。该项目的目的是确定可以在药理上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。我们将测试在血管系统中，一种名为SIRT1的蛋白质会介导多面血管保护作用的假设。我们认为，通过饮食限制或通过基因工程对SIRT1诱导SIRT-1的治疗方法可以在老年小鼠中发挥显着的血管保护作用。