Humans with atherosclerosis have impaired ABCA1 cholesterol efflux and enhanced high-density lipoprotein oxidation by myeloperoxidase.
Humans with atherosclerosis have impaired ABCA1 cholesterol efflux and enhanced high-density lipoprotein oxidation by myeloperoxidase.
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DOI：
10.1161/circresaha.114.303454
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发表时间：
2014-05-23
影响因子：
20.1
通讯作者：
Heinecke JW
中科院分区：
文献类型：
--
作者：
Shao B;Tang C;Sinha A;Mayer PS;Davenport GD;Brot N;Oda MN;Zhao XQ;Heinecke JW
培养的巨噬细胞的HDL外排能力与CAD状态有强烈的负相关性，表明受损的固醇外排能力可能是动脉粥样硬化负荷的标志物，也可能是介导者。然而，导致甾醇外排能力受损的机制仍然知之甚少。确定髓过氧化物酶介导的apoA-I（主要HDL蛋白）氧化损伤与HDL通过ABCA 1途径清除细胞胆固醇的能力之间的关系。我们对对照组和稳定型冠状动脉疾病或急性冠状动脉综合征患者的apoA-I位点特异性氧化和HDL的ABCA 1胆固醇流出能力进行了定量。CAD和ACS受试者的氯化酪氨酸-192和氧化蛋氨酸-148水平高于对照组。相比之下，血浆MPO水平在各组之间没有差异。来自CAD和ACS受试者的HDL比来自对照受试者的HDL更不能够接受来自表达ABCA 1的细胞的胆固醇。氯化酪氨酸和氧化蛋氨酸水平与ABCA 1外排能力呈负相关，与动脉粥样硬化疾病状态呈正相关。在调整HDL-胆固醇水平后，这些差异仍然显着。我们的观察结果表明，MPO可能有助于产生功能障碍的HDL与受损的ABCA 1流出能力在人类动脉粥样硬化。循环HDL中的氯酪氨酸和氧化蛋氨酸的定量可能是独立于HDL-胆固醇的心血管疾病风险的有用指标。
The efflux capacity of HDL with cultured macrophages associates strongly and negatively with CAD status, indicating that impaired sterol efflux capacity might be a marker—and perhaps mediator—of atherosclerotic burden. However, the mechanisms that contribute to impaired sterol efflux capacity remain poorly understood. To determine the relationship between myeloperoxidase-mediated oxidative damage to apoA-I, the major HDL protein, and the ability of HDL to remove cellular cholesterol by the ABCA1 pathway. We quantified both site-specific oxidation of apoA-I and HDL’s ABCA1 cholesterol efflux capacity in control subjects and subjects with stable coronary artery disease or acute coronary syndrome. The CAD and ACS subjects had higher levels of chlorinated tyrosine-192 and oxidized methionine-148 than the control subjects. In contrast, plasma levels of MPO did not differ between the groups. HDL from the CAD and ACS subjects was less able to accept cholesterol from cells expressing ABCA1 than HDL from control subjects. Levels of chlorinated tyrosine and oxidized methionine associated inversely with ABCA1 efflux capacity and positively with atherosclerotic disease status. These differences remained significant after adjusting for HDL-cholesterol levels. Our observations indicate that MPO may contribute to the generation of dysfunctional HDL with impaired ABCA1 efflux capacity in humans with atherosclerosis. Quantification of chlorotyrosine and oxidized methionine in circulating HDL might be useful indicators of the risk of cardiovascular disease that are independent of HDL-cholesterol.