SIRT1, Polyphenols, and Endothelial Oxidants

氧化剂增加与胰岛素抵抗、代谢综合征和易患 动脉粥样硬化这个实验室已经证明，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），包括内皮型一氧化氮合酶 （eNOS）、肌浆网钙ATP酶、p21 ras和锰超氧化物歧化酶。这些 OPTM包括酪氨酸硝化和特定氨基酸残基的半胱氨酸磺基氧化， 与细胞功能障碍有关在内皮功能的一个关键例子中，高葡萄糖氧化了氧化还原- 敏感的硫醇锌通常结合eNOS二聚体，导致eNOS功能障碍。我们的初步 研究已经确定了另一种潜在的氧化剂靶点，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，包括 红葡萄酒成分白藜芦醇直接激活SIRT-1并模拟热量限制的效果， 最近，其他人和我们也显示它们可以减轻体重、高脂血症、粘附分子 表达、氧化剂和动脉粥样硬化。我们发现多酚能刺激AMP- 活化蛋白激酶（AMPK），并涉及AMPK介导高脂血症和 糖尿病小鼠的动脉粥样硬化。连同该计划中的其他项目，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和抑制 SIRT 1，导致AMPK活性下调和内皮功能障碍， 代谢综合征此外，我们认为多酚刺激SIRT 1/LKB 1/AMPK/ eNOS信号转导维持内皮功能、减少氧化剂和抑制粘附 分子表达、凋亡和动脉粥样硬化形成。我们的目标是确定，1）向下的作用， SIRT 1/LKB 1/ AMPK/eNOS信号通路在介导氧化剂作用和对氧化应激反应中的上调 多酚，2）在暴露于氧化剂过程中SIRT-1中发生了什么OPTM，以及3）SIRT 1，LKB 1 和eNOS在多酚类物质对脂肪喂养的大鼠炎症、氧化剂和动脉粥样硬化形成的治疗作用中的作用 小鼠

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.