SIRT1, Polyphenols, and Endothelial Oxidants

SIRT1、多酚和内皮氧化剂

基本信息

批准号：
7596514
负责人：
RICHARD A COHEN
金额：
$ 39.92万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-15 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7596514
关键词：
3-nitrotyrosine 5&apos -AMP-activated protein kinase Abbreviations Accounting Acetyl-CoA Carboxylase Adhesions Adverse effects Amino Acids Anti-Inflammatory Agents Anti-inflammatory Antibodies Antioxidants Apoptosis Apoptotic Area Arterial Fatty Streak Atherosclerosis Attention Binding Blood Vessels Ca(2+)-Calmodulin Dependent Protein Kinase CaM kinase I activator Calcium Caloric Restriction Cattle Cell Adhesion Molecules Cells Chronic Cysteine Detection Diabetes Mellitus Diabetic mouse Diet Down-Regulation Endothelial Cells Endothelium Exposure to Fatty acid glycerol esters Functional disorder Glucose Histone Deacetylase Human Hyperlipidemia Inflammation Insulin Resistance Insulin-Dependent Diabetes Mellitus Intercellular adhesion molecule 1 Label Laboratories Leukocytes Longevity Low Density Lipoprotein Receptor Manganese Superoxide Dismutase Mass Spectrum Analysis Mediating Metabolic syndrome Methods Mus Mutant Strains Mice Nitric Oxide Nitrogen Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Oxidants Oxidation-Reduction Oxygen Pathway interactions Peroxonitrite Phosphotransferases Post-Translational Protein Processing Predisposition Proteins Recombinants Resveratrol Role STK11 gene Signal Transduction Superoxide Dismutase Superoxides Therapeutic Effect Tissues Tyrosine Umbilical vein Up-Regulation Vascular Cell Adhesion Molecule-1 Vasodilation Weight Zinc adenylate kinase aortic arch atherogenesis dimer feeding human NOS2A protein human NOS3 protein imidazolecarboxamide loss of function neurotensin mimic 1 nitration oxidant stress oxidation oxidized low density lipoprotein polyphenol prevent programs red wine response riboside sarcoplasmic reticulum calcium ATPase

项目摘要

Increased oxidants are associated with insulin resistance, the metabolic syndrome, and a predisposition to atherosclerosis. This laboratory has demonstrated that the increase in oxidants causes oxidative post- translational modifications (OPTM) in key vascular cell proteins, including endothelial nitric oxide synthase (eNOS), the sarcoplasmic reticulum calcium ATPase, p21ras, and manganese superoxide dismutase. These OPTM including tyrosine nitration and cysteine sulfoxidation of specific amino acid residues have been implicated in cellular dysfunction. In an example key to endothelial function, high glucose oxidizes the redox- sensitive zinc thiolate that normally binds eNOS dimers, resulting in eNOS dysfunction. Our preliminary studies have identified another potential oxidant target, sirtuin-1 (SIRT-1), a class III histone deacetylase that is thought to be responsible for the increased life span caused by caloric restriction. Polyphenols, including the red wine component, resveratrol, directly activate SIRT-1 and mimic the effects of caloric restriction, and they have also recently been shown by others and us to reduce weight, hyperlipidemia, adhesion molecule expression, oxidants, and atherosclerosis in fat-fed mice. We discovered that polyphenols stimulate AMP- activated protein kinase (AMPK), and implicated AMPK in mediating improvements in hyperlipidemia and atherosclerosis in diabetic mice. Together with other projects within this program, we now propose that chronic oxidant stress associatedwith the metabolic syndrome can directly target and inactivate SIRT1, contributing to the down-regulation of AMPK activity and endothelial dysfunction observed in the metabolic syndrome. In addition, we propose that polyphenols stimulate SIRT1/LKB1/AMPK/ eNOS signaling to maintain endothelial function, decrease oxidants, and suppressadhesion molecule expression, apoptosis, and atherogenesis. Our aims are to determine, 1) the role of down- and up-regulation of SIRT1/LKB1/ AMPK/eNOS signaling in mediating the effect of oxidants and the response to polyphenols, 2) what OPTM occur in SIRT-1 during exposure to oxidants, and 3) the role of SIRT1,LKB1 and eNOS in the therapeutic effect of polyphenols on inflammation, oxidants, and atherogenesis in fat-fed mice.

氧化剂增加与胰岛素抵抗、代谢综合征和易患糖尿病的倾向有关动脉粥样硬化。该实验室已证明氧化剂的增加会导致氧化后关键血管细胞蛋白的翻译修饰 (OPTM)，包括内皮一氧化氮合酶 (eNOS)、肌浆网钙 ATP 酶、p21ras 和锰超氧化物歧化酶。这些 OPTM 包括特定氨基酸残基的酪氨酸硝化和半胱氨酸磺化氧化与细胞功能障碍有关。在内皮功能的一个关键示例中，高葡萄糖会氧化氧化还原- 敏感的硫醇锌通常与 eNOS 二聚体结合，导致 eNOS 功能障碍。我们的初步研究发现了另一种潜在的氧化剂靶标，sirtuin-1 (SIRT-1)，一种 III 类组蛋白脱乙酰酶，被认为是热量限制导致寿命延长的原因。多酚类物质，包括红酒成分白藜芦醇直接激活 SIRT-1 并模仿热量限制的效果，并且最近其他人和我们也证明它们可以减轻体重、高脂血症、粘附分子脂肪喂养小鼠的表达、氧化剂和动脉粥样硬化。我们发现多酚可以刺激 AMP- 激活蛋白激酶（AMPK），并暗示 AMPK 介导高脂血症和糖尿病小鼠的动脉粥样硬化。与该计划中的其他项目一起，我们现在建议与代谢综合征相关的慢性氧化应激可以直接靶向并失活 SIRT1，有助于下调 AMPK 活性和观察到的内皮功能障碍代谢综合征。此外，我们认为多酚可以刺激 SIRT1/LKB1/AMPK/ eNOS 信号传导维持内皮功能、减少氧化剂和抑制粘附分子表达、细胞凋亡和动脉粥样硬化。我们的目标是确定：1) 下层和下层的作用 SIRT1/LKB1/ AMPK/eNOS 信号传导上调介导氧化剂的作用及其反应多酚，2) 暴露于氧化剂期间 SIRT-1 中会发生什么 OPTM，以及 3) SIRT1、LKB1 的作用和 eNOS 在多酚对脂肪喂养的炎症、氧化剂和动脉粥样硬化的治疗作用中的作用老鼠。