Molecular Mechanisms for Dysfunctional High Density Lipoprotein (HDL)

描述(由申请人提供)：人们普遍认为高密度脂蛋白(高密度脂蛋白)通过从动脉细胞中去除多余的胆固醇来预防动脉粥样硬化。最近的研究表明，高密度脂蛋白在体内也具有抗炎和抑制脂质氧化的作用。这些特性可能对高密度脂蛋白抑制动脉粥样硬化的能力有很大贡献。炎症被认为是将高密度脂蛋白转化为一种功能失调的形式，从而失去了这些抗动脉粥样硬化的作用。 了解功能失调的高密度脂蛋白的作用可能会导致动脉粥样硬化和其他炎症性疾病的新诊断和治疗方法。然而，导致高密度脂蛋白功能失调的潜在因素仍然知之甚少。一个重要的途径可能涉及髓过氧化物酶(MPO)对高密度脂蛋白的氧化损伤。我们已经证明，MPO氧化载脂蛋白A-L会损害载脂蛋白通过ABCA1途径清除细胞内胆固醇的能力，并且在体内高密度脂蛋白是MPO损伤的靶点。此外，关于正常和功能失调的高密度脂蛋白中携带的蛋白质的特性，人们知之甚少。我们已经使用鸟枪式蛋白质组学来测试这一假设，即高密度脂蛋白可能携带对其心脏保护活性做出先前未被怀疑的贡献的蛋白质。我们的观察表明，在心血管疾病患者中，高密度脂蛋白携带着一种独特的蛋白质，这些蛋白质可能对高密度脂蛋白的促炎和抗炎特性做出了以前未被怀疑的贡献。 因此，我们建议验证这一假说，即MPO对载脂蛋白A-L的定点氧化和高密度脂蛋白蛋白质组成的有害变化是人类产生功能障碍的高密度脂蛋白的分子机制。我们的具体目标是：i)确定高密度脂蛋白的载脂蛋白A-L在有心血管疾病风险的人类中是否被氧化为靶向；ii)确定人类载脂蛋白A-L的定点氧化是否与载脂蛋白通过ABCA1和Abcg1途径清除细胞胆固醇的能力丧失相关；iii)确定促炎和抗炎蛋白是否有助于在人类中产生功能失调的高密度脂蛋白。

DESCRIPTION (provided by applicant): It is widely believed that high density lipoprotein (HDL) protects against atherosclerosis by removing excess cholesterol from arterial cells. Recent studies indicate that HDL is also anti-inflammatory and inhibits lipid oxidation in vivo. These properties may contribute significantly to HDL's ability to inhibit atherosclerosis. Inflammation has been proposed to convert HDL to a dysfunctional form that loses these antiatherogenic effects. Understanding the role of dysfunctional HDL may lead to new diagnostic and therapeutic approaches to atherosclerosis and other inflammatory conditions. However, the underlying factors that render HDL dysfunctional remain poorly understood. One important pathway may involve oxidative damage to HDL by myeloperoxidase (MPO). We have shown that oxidation of apoA-l by MPO impairs the apolipoprotein's ability to remove cellular cholesterol by the ABCA1 pathway, and that HDL is targeted for damage by MPO in vivo. Furthermore, remarkably little is known regarding the identity of proteins that are carried in normal and dysfunctional HDL. We have used shotgun proteomics to test the hypothesis that HDL might carry proteins that make a previously unsuspected contribution to its cardioprotective activity. Our observations suggest that HDL carries a unique cargo of proteins in CVD subjects and that these proteins might make previously unsuspected contributions to the pro- and anti-inflammatory properties of HDL. We therefore propose to test the hypothesis that site-specific oxidation of apoA-l by MPO and deleterious alterations in the protein composition of HDL are molecular mechanisms for generating dysfunctional HDL in humans. Our specific aims are: i) Establish whether apolipoprotein A-l of HDL is targeted for oxidation in humans at risk for cardiovascular disease, ii) Determine whether site-specific oxidation of apoA-l in humans associates with loss of the apolipoprotein's ability to remove cellular cholesterol by the ABCA1 and ABCG1 pathways, iii) Determine whether pro- and anti-inflammatory proteins help generate dysfunctional HDL in humans.