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发生率较高而引起的急性缺血性综合征是糖尿病（DM）的常见并发症。动脉粥样硬化的氧化修饰假说预测血管壁的氧化事件负责动脉粥样硬化病变的开始和进展。由于糖尿病是一种氧化应激升高的状态，因此糖尿病中动脉粥样硬化的加速和动脉粥样硬化血栓形成的增加被认为是由于氧化修饰的增加。矛盾的是，减少糖尿病患者动脉粥样硬化引起的心血管事件的抗氧化策略失败了，可能是由于患者选择的不足。大剂量抗氧化治疗可能只对氧化应激水平特别高的个体有益。在体外和体内实验中，我们已经证明，粘连珠蛋白（Hp）基因的2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Hp 1-1糖尿病患者相比，Hp 2-2基因型的糖尿病患者心血管事件的发生率增加了500%。基于这种Hp基因型与氧化应激之间的关联，我们提出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对这种方法进行了前瞻性测试，发现维生素E抗氧化治疗可显著降低Hp 2-2糖尿病患者的动脉粥样硬化血栓形成。我们假设Hp 2-2基因型与DM相互作用，促进HDL氧化修饰和功能障碍，这是Hp 2-2- hb复合物与HDL直接相关的结果。为了验证我们的假设，我们设计了机制和介入性研究，使用了一种独特的小鼠模型，表达了来自ICARE的Hp 2蛋白和人库血清，以及两项前瞻性介入性研究。具体目的是评估糖尿病中Hp基因型与HDL结构和功能之间的关系（SA#1）；确定Hp-Hb复合物如何与HDL相关联，以及阻断这种关联是否可以减少HDL氧化并改善HDL功能（SA#2）；并证明抗氧化剂可以改善Hp 2-2 DM的HDL功能（SA#3）。这项研究的结果将揭示Hp基因型与糖尿病相关心血管疾病之间的机制相关性，从而促进药物基因组学方法的应用，以确定哪些患者将受益于抗氧化治疗。

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.