Thukkani Arun K, McHowat Jane, Hsu Fong-Fu, Brennan Marie-Luise, Hazen Stanley L, Ford David A
Department of Biochemistry and Molecular Biology, St Louis University Sciences Center, St Louis, MO, USA.
Circulation. 2003 Dec 23;108(25):3128-33. doi: 10.1161/01.CIR.0000104564.01539.6A. Epub 2003 Nov 24.
A role for myeloperoxidase (MPO) as a mediator of coronary artery disease and acute coronary syndromes has recently received considerable attention. Although active MPO and hypochlorite-modified proteins and peptides have been detected in human atherosclerotic lesions, detection of novel chlorinated oxidized lipid species with proatherogenic properties in vivo has not yet been reported. In this study we show that MPO-generated reactive chlorinating species promote selective oxidative cleavage of plasmalogens, liberating alpha-chloro fatty aldehydes and unsaturated lysophosphatidylcholine in human atherosclerotic lesions.
Stable isotope dilution gas chromatography-mass spectrometry methods were used to identify and quantitate the alpha-chloro fatty aldehyde, 2-chlorohexadecanal, in atherosclerotic versus normal human aorta. Compared with normal aorta, 2-chlorohexadecanal levels were elevated more than 1400-fold in atherosclerotic tissues. Parallel electrospray ionization mass spectrometry studies confirmed 34- and 20-fold increases in the plasmalogen cooxidation products, unsaturated lysophosphatidylcholine molecular species containing linoleic and arachidonic acid, respectively, within atherosclerotic compared with normal aorta. Unsaturated lysophosphatidylcholine containing docosahexaenoic acid was also detected in atherosclerotic but not in normal aorta. Exposure of primary human coronary artery endothelial cells to plasmalogen-derived lysophosphatidylcholine molecular species produced marked increases in P-selectin surface expression.
The present studies demonstrate that plasmalogens are attacked by MPO-derived reactive chlorinating species within human atheroma. The resultant species formed, alpha-chloro fatty aldehydes and unsaturated lysophospholipids, possess proatherogenic properties, as shown by induction of P-selectin surface expression in primary human coronary artery endothelial cells.
髓过氧化物酶（MPO）作为冠状动脉疾病和急性冠状动脉综合征的介质，最近受到了广泛关注。尽管在人类动脉粥样硬化病变中已检测到活性MPO以及次氯酸盐修饰的蛋白质和肽，但尚未有关于体内具有促动脉粥样硬化特性的新型氯化氧化脂质物种的检测报道。在本研究中，我们发现MPO产生的活性氯化物种可促进缩醛磷脂的选择性氧化裂解，在人类动脉粥样硬化病变中释放α-氯代脂肪醛和不饱和溶血磷脂酰胆碱。
采用稳定同位素稀释气相色谱-质谱法，对动脉粥样硬化的人类主动脉与正常人类主动脉中的α-氯代脂肪醛2-氯十六醛进行鉴定和定量。与正常主动脉相比，动脉粥样硬化组织中2-氯十六醛水平升高超过1400倍。平行的电喷雾电离质谱研究证实，与正常主动脉相比，动脉粥样硬化组织中缩醛磷脂共氧化产物（分别含有亚油酸和花生四烯酸的不饱和溶血磷脂酰胆碱分子物种）增加了34倍和20倍。在动脉粥样硬化组织中还检测到了含有二十二碳六烯酸的不饱和溶血磷脂酰胆碱，而正常主动脉中未检测到。将原代人冠状动脉内皮细胞暴露于缩醛磷脂衍生的溶血磷脂酰胆碱分子物种后，P-选择素表面表达显著增加。
本研究表明，在人类动脉粥样硬化斑块中，缩醛磷脂受到MPO衍生的活性氯化物种的攻击。所形成的产物α-氯代脂肪醛和不饱和溶血磷脂具有促动脉粥样硬化特性，这在原代人冠状动脉内皮细胞中P-选择素表面表达的诱导中得到了证实。
