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ATPase、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亚硫氧化。 与细胞功能障碍有关。在一个对内皮功能至关重要的例子中，高糖氧化了氧化还原- 敏感的硫代锌，通常与eNOS二聚体结合，导致eNOS功能障碍。我们的预赛 研究已经确定了另一个潜在的氧化靶点，sirtuin-1(SIRT-1)，一种III型组蛋白脱乙酰基酶 被认为是卡路里限制导致寿命延长的原因。多酚，包括 红酒成分白藜芦醇直接激活SIRT-1，模拟卡路里限制的效果，以及 最近，其他人和我们也证明它们可以减轻体重、高脂血症、黏附分子 脂肪喂养小鼠的表达、氧化剂与动脉粥样硬化。我们发现，多酚能刺激AMP- 活化蛋白激酶(AMPK)，并参与AMPK介导的高脂血症的改善和 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直接靶向和失活 SIRT1，参与AMPK活性下调和内皮功能障碍 代谢综合征。此外，我们还提出了多酚刺激SIRT1/LKB1/AMPK/的机制。 ENOS信号转导维持内皮功能，减少氧化剂，抑制黏附 分子表达、细胞凋亡和动脉粥样硬化形成。我们的目标是确定，1)羽绒的作用-和 SIRT1/LKB1/AMPK/eNOS信号上调在介导氧化剂的作用及对 多酚，2)SIRT-1在接触氧化剂时发生了什么OPTM，以及3)SIRT1，LKB1的作用 内皮型一氧化氮合酶在多酚对高脂饮食大鼠炎症、氧化剂和动脉粥样硬化形成中的作用 老鼠。

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.