Oxidation Hypothesis Revisited: Haptoglobin Genotype & Diabetic Atherosclerosis

项目摘要 由于斑块破裂和血栓形成的发生率较高的急性缺血综合征是常见的 糖尿病(DM)相关并发症。氧化修饰假说 动脉粥样硬化预测，血管壁中的氧化事件是导致动脉粥样硬化 动脉粥样硬化病变的进展。由于糖尿病代表一种高度氧化应激的状态， 糖尿病患者动脉粥样硬化加速和动脉粥样硬化血栓形成增加被认为是由于 氧化修饰。矛盾的是，抗氧化剂策略可以减少 糖尿病的动脉粥样硬化已经失败，可能是因为患者选择的性质不充分。高剂量 抗氧化疗法可能只对氧化应激水平特别高的人有好处。我们 已经在体外和体内证明，结合珠蛋白基因的2个等位基因与高水平的 糖尿病中的氧化应激。在临床研究中，我们发现具有Hp 2-2基因的DM个体有AS 与HP 1-1 DM患者相比，心血管事件的发生率增加了500%。在此基础上 幽门螺杆菌基因分型与氧化应激的关系我们已经提出了一种药物基因组学方法 确定哪些人将从抗氧化剂治疗中受益。我们最近对此进行了前瞻性的测试。 在一项双盲安慰剂对照试验中发现维生素E的抗氧化疗法 显著降低HP2-2 DM患者的动脉粥样硬化血栓形成。 我们假设HP2-2基因与DM相互作用，促进高密度脂蛋白氧化修饰和 Hp 2-2-Hb复合体与高密度脂蛋白直接相关所致的功能障碍。为了检验我们的假设，我们 我使用一种独特的表达Hp 2的小鼠模型设计了机制和干预性研究 来自ICARE的蛋白质和人血清库以及两项前瞻性干预研究。 具体目的是评估HP基因型与高密度脂蛋白结构和功能之间的关系。 DM(SA#1)；确定Hp-Hb复合体如何与高密度脂蛋白关联，以及是否阻止这种关联 能减少高密度脂蛋白氧化，改善高密度脂蛋白功能(SA#2)；并证明高密度脂蛋白功能可以 通过抗氧化剂(SA#3)改善HP 2-2 DM。这项研究的结果将有助于阐明 幽门螺杆菌基因与糖尿病相关心血管疾病的相关性 应用药物基因组学方法确定哪些患者将受益于抗氧化剂 治疗。

Project Abstract Acute ischemic syndromes due to a higher incidence of plaque rupture and thrombosis are common complications associated with Diabetes Mellitus (DM). The oxidative modification hypothesis of atherosclerosis predicts that oxidative events in the vessel wall are responsible for the initiation and progression of atherosclerotic lesions. As DM represents a state of heightened oxidative stress, the accelerated atherosclerosis and increased atherothrombosis in DM are thought to be due to increased oxidative modifications. Paradoxically, anti-oxidant strategies to reduce cardiovascular events from atherosclerosis in DM have failed, possibly due to the inadequate nature of patient selection. High dose antioxidant therapy may only provide benefit to individuals with particularly high levels of oxidative stress. We have shown, in vitro and in vivo, that the 2 allele of the Haptoglobin (Hp) gene is associated with high levels of oxidative stress in DM. In clinical studies we have found that DM individuals with the Hp 2-2 genotype have as much as a 500% increase in cardiovascular events as compared to Hp 1-1 DM individuals. Based on this association of the Hp genotype and oxidative stress we have suggested a pharmacogenomic approach for identifying individuals who will benefit from antioxidant therapy. We have recently prospectively tested this approach in a double-blind placebo controlled trial and found that antioxidant therapy with vitamin E significantly reduced atherothrombosis in Hp 2-2 DM individuals. We hypothesize that the Hp 2-2 genotype interacts with DM to promote HDL oxidative modification and dysfunction as a result of the direct association of the Hp 2-2-Hb complex with HDL. To test our hypothesis we have designed both mechanistic and interventional studies using a unique mouse model expressing the Hp 2 protein and human banked serum from ICARE and two prospective interventional studies.. The specific aims are to assess the relationship between the Hp genotype and HDL structure and function in DM (SA#1); to determine how the Hp-Hb complex associates with HDL and whether blocking this association can decrease HDL oxidation and improve HDL function (SA#2); and to demonstrate that HDL function can be improved in Hp 2-2 DM by antioxidants (SA#3). Results from this study will shed light on the mechanistic correlation between the Hp genotype and cardiovascular diseases associated with DM, thus promoting application of a pharmacogenomic approach to identifying patients who will benefit from antioxidative treatment.