Oxidation Hypothesis Revisited: Haptoglobin Genotype & Diabetic Atherosclerosis

描述(由申请人提供)：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与糖尿病(DM)相关的常见并发症。动脉粥样硬化的氧化修饰假说认为，血管壁上的氧化事件与动脉粥样硬化病变的发生和发展有关。由于糖尿病代表氧化应激的一种状态，糖尿病患者动脉粥样硬化的加速和动脉粥样硬化血栓的增加被认为是由于氧化修饰的增加。矛盾的是，减少糖尿病动脉粥样硬化心血管事件的抗氧化剂策略失败了，可能是因为患者选择的性质不充分。大剂量的抗氧化剂治疗可能只对氧化应激水平特别高的个人有利。我们已经在体外和体内证明，结合珠蛋白(HP)基因的2个等位基因与糖尿病患者的高水平氧化应激有关。在临床研究中，我们发现与Hp1-1 DM患者相比，携带HP2-2基因的DM患者心血管事件的发生率增加了500%。基于HP基因和氧化应激的这种关联，我们建议了一种药物基因组学方法来确定将从抗氧化治疗中受益的个体。我们最近在一项双盲安慰剂对照试验中前瞻性地测试了这种方法，发现维生素E的抗氧化治疗显著减少了HP 2-2 DM患者的动脉粥样硬化血栓形成。我们推测，由于HP2-2-Hb复合体与高密度脂蛋白的直接关联，HP2-2与DM相互作用，从而促进了高密度脂蛋白的氧化修饰和功能障碍。为了验证我们的假设，我们设计了机械性和干预性研究，使用一种独特的表达HP2蛋白和ICARE人库血清的小鼠模型，以及两项前瞻性干预研究。本研究的具体目的是评估Hp基因与糖尿病(SA#1)高密度脂蛋白结构和功能的关系；确定Hp-Hb复合体与高密度脂蛋白的关系，以及阻断这种联系是否可以减少高密度脂蛋白的氧化和改善高密度脂蛋白功能(低密度脂蛋白氧化)(SA#2)；以及证明抗氧化剂(SA#3)可以改善HP2-2 DM的高密度脂蛋白功能。这项研究的结果将阐明HP基因与糖尿病相关心血管疾病之间的机制关联，从而促进药物基因组学方法的应用，以确定哪些患者将从抗氧化治疗中受益。 公共卫生相关性：我们已经证明，结合珠蛋白2-2基因与糖尿病患者心血管事件发生率的增加有关。我们以前曾提出，这可能是通过高密度脂蛋白功能缺陷来调节的。在这个项目中，我们将研究HP2-2基因促进高密度脂蛋白功能障碍的机制，以及抗氧化治疗如何预防和逆转这一过程。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: We have shown that the Haptoglobin 2-2 geneotype is associated with an increased incidence of cardiovascular events in individuals with Diabetes Mellitus. We have previously proposed that this may be mediated thru defective HDL function. In this project we will study the mechanism through which the Hp 2-2 genotype promotes HDL dysfunction and how antioxidative therapy can prevent and reverse this process.