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（HDL）通过从动脉细胞中清除过量的胆固醇来防止动脉粥样硬化。最近的研究表明，HDL也是抗炎和抑制体内脂质氧化。这些特性可能对HDL抑制动脉粥样硬化的能力有重要贡献。已经提出炎症将HDL转化为失去这些抗动脉粥样硬化作用的功能障碍形式。 了解功能失调的HDL的作用可能会导致动脉粥样硬化和其他炎症性疾病的新的诊断和治疗方法。然而，使HDL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HDL的氧化损伤。我们已经表明，MPO对apoA-1的氧化损害了载脂蛋白通过ABCA 1途径去除细胞胆固醇的能力，并且HDL是MPO在体内损伤的靶向。此外，关于正常和功能失调的HDL中携带的蛋白质的身份知之甚少。我们已经使用鸟枪蛋白质组学来测试HDL可能携带的蛋白质对其心脏保护活性做出先前未被怀疑的贡献的假设。我们的观察结果表明，HDL携带一个独特的货物的蛋白质在心血管疾病的科目，这些蛋白质可能使以前未被怀疑的贡献，促和抗炎性质的HDL。 因此，我们建议测试的假设，即MPO和有害的改变，在HDL的蛋白质组成的apoA-1的位点特异性氧化的分子机制，在人类中产生功能失调的HDL。我们的具体目标是：i）确定HDL的载脂蛋白A-I是否靶向于处于心血管疾病风险中的人类中的氧化，ii）确定人类中apoA-I的位点特异性氧化是否与载脂蛋白通过ABCA 1和ABCG 1途径去除细胞胆固醇的能力的丧失相关，iii）确定促炎蛋白和抗炎蛋白是否有助于在人类中产生功能失调的HDL。

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.