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）通过去除动脉细胞中多余的胆固醇来防止动脉粥样硬化。最近的研究表明，HDL 还具有抗炎作用并抑制体内脂质氧化。这些特性可能对 HDL 抑制动脉粥样硬化的能力有显着贡献。有人提出，炎症会将高密度脂蛋白转化为功能失调的形式，从而失去这些抗动脉粥样硬化作用。 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 HDL 功能障碍的根本因素仍然知之甚少。一种重要途径可能涉及髓过氧化物酶 (MPO) 对 HDL 的氧化损伤。我们已经证明，MPO 对 apoA-1 的氧化会损害载脂蛋白通过 ABCA1 途径去除细胞胆固醇的能力，并且 HDL 在体内是 MPO 损伤的目标。此外，对于正常和功能失调的 HDL 中携带的蛋白质的身份知之甚少。我们使用鸟枪法蛋白质组学来检验 HDL 可能携带的蛋白质对其心脏保护活性做出以前未曾怀疑的贡献这一假设。我们的观察表明，HDL 在 CVD 受试者中携带着独特的蛋白质，这些蛋白质可能对 HDL 的促炎和抗炎特性做出了以前未曾怀疑的贡献。 因此，我们建议检验以下假设：MPO 对 apoA-1 的位点特异性氧化和 HDL 蛋白质组成的有害改变是在人类中产生功能失调的 HDL 的分子机制。我们的具体目标是：i) 确定 HDL 的载脂蛋白 A-1 是否是有心血管疾病风险的人类的氧化目标，ii) 确定人类 apoA-1 的位点特异性氧化是否与载脂蛋白通过 ABCA1 和 ABCG1 途径去除细胞胆固醇的能力丧失相关，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.