Site-specific oxidation of apolipoprotein A-I impairs cholesterol export by ABCA1, a key cardioprotective function of HDL.
Site-specific oxidation of apolipoprotein A-I impairs cholesterol export by ABCA1, a key cardioprotective function of HDL.
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DOI：
10.1016/j.bbalip.2011.11.011
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发表时间：
2012-03
期刊：
影响因子：
--
通讯作者：
Shao B
中科院分区：
文献类型：
--
作者：
Shao B
剥夺高密度脂蛋白心脏保护特性的机制还知之甚少。一种可能的途径涉及髓过氧化物酶(MPO)对高密度脂蛋白的氧化损伤，髓过氧化物酶是人动脉壁巨噬细胞分泌的一种血红素酶。质谱分析表明，MPO的两个特征产物3-氯酪氨酸和3-硝基酪氨酸的水平在从既往心血管疾病患者中分离出来的高密度脂蛋白中升高。当主要的高密度脂蛋白ApoA-I(apoA-I)被MPO氧化时，其通过膜相关的ATP结合盒转运体A1(ABCA1)途径促进细胞胆固醇外流的能力减弱。生化研究表明，载脂蛋白A-I中特定酪氨酸和蛋氨酸残基的氧化导致了ABCA1活性的丧失。另一种产生功能失调的高密度脂蛋白的潜在机制是通过反应性羰基对载脂蛋白A-I进行共价修饰，这与动脉粥样硬化和糖尿病血管疾病有关。事实上，用丙二醛(MDA)或丙烯醛修饰apoA-I也显著削弱了脂蛋白通过ABCA1途径促进细胞胆固醇外流的能力。串联质谱分析表明，这些反应性羰基针对载脂蛋白A-I C末端的特定赖氨酸残基。重要的是，免疫化学分析表明，从人类动脉粥样硬化病变中分离的高密度脂蛋白中，丙二醛-蛋白质加合物的水平升高。此外，apoA-I与丙烯醛加合物在此类病变中共定位。因此，脂质过氧化产物可能在体内特异性地修饰高密度脂蛋白。我们的观察结果支持这样的假设，即MPO和反应性羰基可能会在人类中产生功能失调的高密度脂蛋白。
The mechanisms that deprive HDL of its cardioprotective properties are poorly understood. One potential pathway involves oxidative damage of HDL proteins by myeloperoxidase (MPO) a heme enzyme secreted by human artery wall macrophages. Mass spectrometric analysis demonstrated that levels of 3-chlorotyrosine and 3-nitrotyrosine—two characteristic products of MPO—are elevated in HDL isolated from patients with established cardiovascular disease. When apolipoprotein A-I (apoA-I), the major HDL protein, is oxidized by MPO, its ability to promote cellular cholesterol efflux by the membrane-associated ATP-binding cassette transporter A1 (ABCA1) pathway is diminished. Biochemical studies revealed that oxidation of specific tyrosine and methionine residues in apoA-I contributes to this loss of ABCA1 activity. Another potential mechanism for generating dysfunctional HDL involves covalent modification of apoA-I by reactive carbonyls, which have been implicated in atherogenesis and diabetic vascular disease. Indeed, modification of apoA-I by malondialdehyde (MDA) or acrolein also markedly impaired the lipoprotein’s ability to promote cellular cholesterol efflux by the ABCA1 pathway. Tandem mass spectrometric analyses revealed that these reactive carbonyls target specific Lys residues in the C-terminus of apoA-I. Importantly, immunochemical analyses showed that levels of MDA-protein adducts are elevated in HDL isolated from human atherosclerotic lesions. Also, apoA-I co-localized with acrolein adducts in such lesions. Thus, lipid peroxidation products might specifically modify HDL in vivo. Our observations support the hypotheses that MPO and reactive carbonyls might generate dysfunctional HDL in humans.
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