Formation of oxysterols during oxidation of low density lipoprotein by peroxynitrite, myoglobin, and copper.
Formation of oxysterols during oxidation of low density lipoprotein by peroxynitrite, myoglobin, and copper.
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发表时间：
1996-11
影响因子：
6.5
通讯作者：
R. Patel;U. Diczfalusy;S. Dzeletovic;M. Wilson;V. Darley-Usmar
中科院分区：
文献类型：
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作者：
R. Patel;U. Diczfalusy;S. Dzeletovic;M. Wilson;V. Darley-Usmar
动脉壁中低密度脂蛋白（LDL）的氧化导致胆固醇氧化产物的形成，这可能导致细胞毒性。不同的机制可能有助于体内LDL氧化，导致胆固醇分子的特征性和特异性修饰。或者，链传播过氧自由基对胆固醇的攻击可能导致氧化产物的相同分布，而不管最初的促氧化机制如何。为了区分这些可能性，我们监测了9氧化固醇的形成过程中LDL氧化，促进铜，肌红蛋白，过氧亚硝酸盐，或偶氮双脒基丙烷。无论使用哪种氧化剂，氧化固醇形成的模式基本相同。所鉴定的产物的产率以7-氧代胆固醇> 7 β-羟基胆固醇> 7 α-羟基胆固醇> 5，6 β-环氧胆固醇> 5，6 α-环氧胆固醇的顺序降低，除了在过氧亚硝酸盐的情况下之外，在过氧亚硝酸盐的情况下，发现5，6 β-环氧胆固醇的产率相对于7-氧代胆固醇更高。或24-，25-，27-羟基胆固醇。LDL中7-氧代胆固醇的浓度水平与蛋白质修饰的程度呈正相关。LDL中的内源性α-生育酚或补充丁基羟基甲苯可防止氧化固醇形成。总之，这些数据表明，在LDL中的胆固醇和蛋白质的氧化发生作为继发性氧化事件的脂肪酸过氧基/烷氧基自由基攻击胆固醇的7-位，并与apoB上的氨基酸。此外，具有致动脉粥样硬化潜力的氧化剂过程，如过氧亚硝酸盐、铜和肌红蛋白能够产生含有细胞毒性介质的氧化LDL。
Oxidation of low density lipoprotein (LDL) in the artery wall leads to the formation of cholesterol oxidation products that may result in cytotoxicity. Different mechanisms could contribute to LDL oxidation in vivo resulting in characteristic and specific modification of the cholesterol molecule. Alternatively, attack on cholesterol by chain propagating peroxyl radicals could result in the same distribution of oxidation products irrespective of the initial pro-oxidant mechanism. To distinguish between these possibilities we have monitored the formation of nine oxysterols during LDL oxidation, promoted by copper, myoglobin, peroxynitrite, or azo bis amidino propane. Regardless of the oxidant used, the pattern of oxysterol formation was essentially the same. The yields of products identified decreased in the order 7-oxocholesterol > 7 beta-hydroxycholesterol > 7 alpha-hydroxycholesterol > 5,6 beta-epoxycholesterol > 5,6 alpha-epoxycholesterol except in the case of peroxynitrite in which case a higher yield of 5, 6 beta-epoxycholesterol relative to 7-oxocholesterol was found. No formation of cholestane 3 beta, 5 alpha, 6 beta-triol, or the 24-,25-,27-hydroxycholesterols was seen. Concentration of 7-oxocholesterol levels in LDL was positively correlated with the degree of protein modification. Endogenous alpha-tocopherol in LDL or supplementation with butylated hydroxytoluene prevented oxysterol formation. Taken together these data indicate that the oxidation of cholesterol and protein in LDL occur as secondary oxidation events consequent on the attack of fatty acid peroxyl/alkoxyl radicals on the 7-position of cholesterol, and with amino acids on apoB. Furthermore, oxidant processes with atherogenic potential, such as peroxynitrite, copper, and myoglobin are capable of producing oxidized LDL containing cytotoxic mediators.