Acrolein impairs ATP binding cassette transporter A1-dependent cholesterol export from cells through site-specific modification of apolipoprotein A-I
Acrolein impairs ATP binding cassette transporter A1-dependent cholesterol export from cells through site-specific modification of apolipoprotein A-I
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DOI：
10.1074/jbc.m508169200
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发表时间：
2005-10-28
影响因子：
4.8
通讯作者：
Heinecke, JW
中科院分区：
文献类型：
--
作者：
Shao, BH;Fu, XY;Heinecke, JW
丙烯醛是一种高活性的α， β -不饱和醛，但控制其与蛋白质上的亲核基团反应的因素仍然知之甚少。脂质过氧化和髓过氧化物酶的苏氨酸氧化是炎症期间丙烯醛的潜在来源。由于这两种途径都与动脉粥样硬化有关，而高密度脂蛋白（HDL）具有抗动脉粥样硬化的作用，因此我们研究了丙烯醛可能针对HDL的主要蛋白载脂蛋白A-I （apoA-I）进行修饰的可能性。串联质谱分析表明，位于apoA-I螺旋10中心附近的赖氨酸226是丙烯醛修饰的主要位点。重要的是，该区域在细胞相互作用和apoA-I转运脂质的能力中起着关键作用。事实上，我们发现丙烯醛将Lys-226转化为N-epsilon-（3-甲基吡啶）赖氨酸与通过atp结合盒转运蛋白A1途径从细胞中减少胆固醇外排有关。在截断的apoA-I的晶体结构中，Glu-234位于lys226附近，这表明带负电荷的残基可能指导蛋白质中特定赖氨酸残基的修饰。最后，免疫组织化学单克隆抗体研究显示apoa - 1与丙烯醛加合物在人类动脉粥样硬化病变中共定位。我们的观察表明丙烯醛可能通过改变apoa - 1中的特定位点干扰HDL正常的逆向胆固醇运输。因此，丙烯醛可能通过阻碍胆固醇从动脉壁清除而促进动脉粥样硬化。
Acrolein is a highly reactive alpha,beta-unsaturated aldehyde, but the factors that control its reactions with nucleophilic groups on proteins remain poorly understood. Lipid peroxidation and threonine oxidation by myeloperoxidase are potential sources of acrolein during inflammation. Because both pathways are implicated in atherogenesis and high density lipoprotein (HDL) is anti-atherogenic, we investigated the possibility that acrolein might target the major protein of HDL, apolipoprotein A-I (apoA-I), for modification. Tandem mass spectrometric analysis demonstrated that lysine 226, located near the center of helix 10 in apoA-I, was the major site modified by acrolein. Importantly, this region plays a critical role in the cellular interactions and ability of apoA-I to transport lipid. Indeed, we found that conversion of Lys-226 to N-epsilon-(3-methylpyridinium) lysine by acrolein associated quantitatively with decreased cholesterol efflux from cells via the ATP-binding cassette transporter A1 pathway. In the crystal structure of truncated apoA-I, Glu-234 lies adjacent to Lys-226, suggesting that negatively charged residues might direct the modification of specific lysine residues in proteins. Finally, immunohistochemical studies with a monoclonal antibody revealed co-localization of apoA-I with acrolein adducts in human atherosclerotic lesions. Our observations suggest that acrolein might interfere with normal reverse cholesterol transport by HDL by modifying specific sites in apoA-I. Thus, acrolein might contribute to atherogenesis by impairing cholesterol removal from the artery wall.