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而导致的急性缺血综合征是常见的 与糖尿病（DM）相关的并发症。氧化修饰假说 动脉粥样硬化预测血管壁中的氧化事件是引发和 动脉粥样硬化病变的进展。由于DM代表氧化应激增强的状态， 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 氧化修饰特别是，抗氧化策略，以减少心血管事件， 糖尿病患者动脉粥样硬化的治疗失败，可能是由于患者选择的不充分。高剂量 抗氧化剂治疗可能仅对具有特别高水平的氧化应激的个体提供益处。我们 已经在体外和体内显示，结合珠蛋白（Hp）基因的2等位基因与高水平的 DM中的氧化应激在临床研究中，我们已经发现，糖尿病患者与Hp 2-2基因型， 与Hp 1-1 DM个体相比，心血管事件增加多达500%。基于此 Hp基因型和氧化应激的关联，我们提出了一种药物基因组学方法， 确定将从抗氧化剂治疗中受益的个体。我们最近进行了前瞻性测试 在一项双盲安慰剂对照试验中， 在Hp 2-2 DM个体中显著降低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， 由于Hp 2-2-Hb复合物与HDL直接结合而导致的功能障碍。为了验证我们的假设， 我设计了一种独特的表达Hp 2的小鼠模型， 来自ICARE和两项前瞻性干预研究的蛋白质和人库血清。 具体目的是评估Hp基因型与HDL结构和功能之间的关系， DM（SA#1）;确定Hp-Hb复合物如何与HDL结合以及是否阻断这种结合 可以减少HDL氧化并改善HDL功能（SA#2）;并证明HDL功能可以 抗氧化剂可改善Hp 2-2 DM（SA#3）。这项研究的结果将阐明 Hp基因型与糖尿病相关的心血管疾病之间的相关性，从而促进 应用药物基因组学方法鉴定将从抗氧化剂中获益的患者 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.