Modification by acrolein, a component of tobacco smoke and age-related oxidative stress, mediates functional impairment of human apolipoprotein E.
Modification by acrolein, a component of tobacco smoke and age-related oxidative stress, mediates functional impairment of human apolipoprotein E.
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DOI：
10.1021/bi700289k
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发表时间：
2007-06
期刊：
影响因子：
2.9
通讯作者：
Shiori Tamamizu‐Kato;J. Y. Wong;V. Jairam;K. Uchida;V. Raussens;H. Kato;J. Ruysschaert;V. Narayanaswami
中科院分区：
文献类型：
--
作者：
Shiori Tamamizu‐Kato;J. Y. Wong;V. Jairam;K. Uchida;V. Raussens;H. Kato;J. Ruysschaert;V. Narayanaswami
蛋白质如载脂蛋白B-100的氧化损伤增加了低密度脂蛋白（LDL）的致动脉粥样硬化性。然而，很少有人知道的潜在氧化损伤载脂蛋白E（apoE），可交换的抗动脉粥样硬化载脂蛋白。ApoE通过调节血浆胆固醇和甘油三酯水平在脂蛋白代谢中起着不可或缺的作用。脂蛋白的肝摄取通过apoE与细胞表面硫酸乙酰肝素蛋白聚糖结合的能力以及通过其22 kDa N-末端结构域（NT）中的碱性残基与脂蛋白受体结合的能力来促进。我们研究了丙烯醛，内源性脂质过氧化的代谢产物和烟草烟雾成分，对重组人apoE 3-NT的构象和功能的影响。丙烯醛引起氧化修饰的apoE 3-NT检测丙烯醛-赖氨酸特异性抗体的蛋白质印迹，和三级构象的改变。丙烯醛修饰损害apoE 3-NT与肝素和LDL受体相互作用的能力。此外，丙烯醛修饰的apoE 3-NT与脂质表面相互作用的能力降低了5倍。我们的数据表明，丙烯醛破坏apoE 3的功能完整性，这可能会干扰其在调节血浆胆固醇稳态的作用。这些观察结果的影响，吸烟和氧化应激介导的心血管和脑血管疾病的发病机制中的作用载脂蛋白E。
Oxidative damage to proteins such as apolipoprotein B-100 increases the atherogenicity of low-density lipoproteins (LDL). However, little is known about the potential oxidative damage to apolipoprotein E (apoE), an exchangeable antiatherogenic apolipoprotein. ApoE plays an integral role in lipoprotein metabolism by regulating the plasma cholesterol and triglyceride levels. Hepatic uptake of lipoproteins is facilitated by apoE's ability to bind with cell surface heparan sulfate proteoglycans and to lipoprotein receptors via basic residues in its 22 kDa N-terminal domain (NT). We investigated the effect of acrolein, an aldehydic product of endogenous lipid peroxidation and a tobacco smoke component, on the conformation and function of recombinant human apoE3-NT. Acrolein caused oxidative modification of apoE3-NT as detected by Western blot with acrolein-lysine-specific antibodies, and tertiary conformational alterations. Acrolein modification impairs the ability of apoE3-NT to interact with heparin and the LDL receptor. Furthermore, acrolein-modified apoE3-NT displayed a 5-fold decrease in its ability to interact with lipid surfaces. Our data indicate that acrolein disrupts the functional integrity of apoE3, which likely interferes with its role in regulating plasma cholesterol homeostasis. These observations have implications regarding the role of apoE in the pathogenesis of smoking- and oxidative stress-mediated cardiovascular and cerebrovascular diseases.