Dever Gary, Wainwright Cherry L, Kennedy Simon, Spickett Corinne M
Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
Acta Biochim Pol. 2006;53(4):761-8. Epub 2006 Nov 27.
The oxidation of low-density lipoprotein (LDL) is thought to contribute to atherogenesis, which is an inflammatory disease involving activation of phagocytic cells. Myeloperoxidase, an enzyme which is able to produce hypochlorous acid (HOCl), is released from these phagocytic cells, and has been found in an active form in atherosclerotic plaques. HOCl can oxidize both the lipid and protein moiety of LDL, and HOCl-modified LDL has been found to be pro-inflammatory, although it is not known which component is responsible for this effect. As HOCl can oxidize lipids to give chlorohydrins, we hypothesized that phospholipid chlorohydrins might have toxic and pro-inflammatory effects. We have formed chlorohydrins from fatty acids (oleic, linoleic and arachidonic acids) and from phospholipids (stearoyl-oleoyl phosphatidylcholine, stearoyl-linoleoyl phosphatidylcholine and stearoyl-arachidonoyl phosphatidylcholine), and investigated various biological effects of these oxidation products. Fatty acid and phospholipid chlorohydrins were found to deplete ATP levels in U937 cells in a concentration-dependent manner, with significant effects observed at concentrations of 25 microM and above. Low concentrations (25 microM) of stearoyl-oleoyl phosphatidylcholine and stearoyl-arachidonoyl phosphatidylcholine chlorohydrins were also found to increase caspase-3 activity. Finally, stearoyl-oleoyl phosphatidylcholine chlorohydrin increased leukocyte adhesion to artery segments isolated from C57Bl/6 mice. These results demonstrate potentially harmful effects of lipid chlorohydrins, and suggest that they may contribute to some of the pro-inflammatory effects that HOCl-modified low density lipoprotein has been found to induce.
低密度脂蛋白（LDL）的氧化被认为会促进动脉粥样硬化的形成，动脉粥样硬化是一种涉及吞噬细胞激活的炎症性疾病。髓过氧化物酶是一种能够产生次氯酸（HOCl）的酶，它从这些吞噬细胞中释放出来，并在动脉粥样硬化斑块中以活性形式被发现。HOCl可以氧化LDL的脂质和蛋白质部分，并且已发现HOCl修饰的LDL具有促炎作用，尽管尚不清楚是哪种成分导致了这种效应。由于HOCl可以将脂质氧化生成氯醇，我们推测磷脂氯醇可能具有毒性和促炎作用。我们已经从脂肪酸（油酸、亚油酸和花生四烯酸）以及磷脂（硬脂酰油酰磷脂酰胆碱、硬脂酰亚油酰磷脂酰胆碱和硬脂酰花生四烯酰磷脂酰胆碱）中生成了氯醇，并研究了这些氧化产物的各种生物学效应。发现脂肪酸和磷脂氯醇以浓度依赖性方式降低U937细胞中的ATP水平，在25 microM及以上的浓度下观察到显著影响。还发现低浓度（25 microM）的硬脂酰油酰磷脂酰胆碱和硬脂酰花生四烯酰磷脂酰胆碱氯醇会增加caspase-3活性。最后，硬脂酰油酰磷脂酰胆碱氯醇增加了白细胞与从C57Bl/6小鼠分离的动脉段的粘附。这些结果证明了脂质氯醇的潜在有害作用，并表明它们可能导致了已发现HOCl修饰的低密度脂蛋白所诱导的一些促炎效应。
