Plasma-advanced oxidation protein products are potent high-density lipoprotein receptor antagonists in vivo.
Plasma-advanced oxidation protein products are potent high-density lipoprotein receptor antagonists in vivo.
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DOI：
10.1161/circresaha.108.193169
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发表时间：
2009-03-27
影响因子：
20.1
通讯作者：
Oettl K
中科院分区：
文献类型：
--
作者：
Marsche G;Frank S;Hrzenjak A;Holzer M;Dirnberger S;Wadsack C;Scharnagl H;Stojakovic T;Heinemann A;Oettl K
晚期氧化蛋白产物（AOPP）由氧化血浆蛋白（尤其是白蛋白）携带，并在肾病和冠状动脉疾病受试者中积累。AOPPs是一种新的氧化应激标志物，在心血管疾病的发生发展中可能具有重要意义。在这里，我们表明，在体外生成的AOPP-白蛋白结合高密度脂蛋白（HDL）受体清道夫受体类B I型（SR-BI）的高亲和力。AOPP-白蛋白与HDL的等摩尔浓度已经阻断了HDL与SR-BI的结合，并有效地抑制了SR-BI介导的胆固醇酯（CE）摄取。有趣的是，被晚期糖基化终产物（AGE-白蛋白）广泛修饰的白蛋白（已知其是一种在肾脏疾病中蓄积的SR-BI配体）仅微弱干扰HDL与SR-BI的结合。此外，AOPP-白蛋白给药使对照小鼠中[3 H]CE-HDL的血浆半衰期增加1.6倍（P=0.01），使感染编码人SR-BI的腺病毒载体的小鼠中[3 H]CE-HDL的血浆半衰期增加8倍（P=0.0003）。此外，从血液透析患者中分离的白蛋白（而不是从健康对照中分离的白蛋白）在体外显著抑制SR-BI介导的HDL-CE转移，这取决于白蛋白的AOPP含量。这些结果表明AOPP-白蛋白在体外和体内有效地阻断SR-BI。因此，HDL-胆固醇的血浆清除率降低可能导致HDL组成异常和慢性肾功能衰竭患者中观察到的心血管高风险。
Advanced oxidation protein products (AOPPs) are carried by oxidized plasma proteins, especially albumin and accumulate in subjects with renal disease and coronary artery disease. AOPPs represent an excellent novel marker of oxidative stress and their roles in the development of cardiovascular disease might be of great importance. Here, we show that in vitro–generated AOPP-albumin binds with high affinity to the high-density lipoprotein (HDL) receptor scavenger receptor class B type I (SR-BI). Already an equimolar concentration of AOPP-albumin to HDL blocked HDL association to SR-BI and effectively inhibited SR-BI–mediated cholesterol ester (CE) uptake. Interestingly, albumin extensively modified by advanced glycation end products (AGE-albumin), which is an established SR-BI ligand known to accumulate in renal disease, only weakly interfered with HDL binding to SR-BI. Furthermore, AOPP-albumin administration increased the plasma half-life of [3H]CE-HDL in control mice 1.6-fold (P=0.01) and 8-fold (P=0.0003) in mice infected with adenoviral vectors encoding human SR-BI. Moreover, albumin isolated from hemodialysis patients, but not albumin isolated from healthy controls, markedly inhibited SR-BI–mediated HDL-CE transfer in vitro dependent on the AOPP content of albumin. These results indicate that AOPP-albumin effectively blocks SR-BI in vitro and in vivo. Thus, depressed plasma clearance of HDL-cholesterol may contribute to the abnormal composition of HDL and the high cardiovascular risk observed in patients with chronic renal failure.