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标题：Macrophage-specific expression of group IIA sPLA2 results in accelerated atherogenesis by increasing oxidative stress
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作者：Tietge, Uwe J. F. ; Pratico, Domenico ; Ding, Tao 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2005
卷号：46
期号：08
页码：1604-1614
DOI：10.1194/jlr.M400469-JLR200
出版社：American Society for Biochemistry and Molecular Biology
摘要：Group IIA secretory phospholipase A₂ (sPLA₂) is an acute-phaseprotein mediating decreased plasma HDL cholesterol and increasedatherosclerosis. This study investigated the impact of macrophage-specificsPLA₂ overexpression on lipoprotein metabolism and atherogenesis.Macrophages from sPLA₂ transgenic mice have 2.5 times increasedrates of LDL oxidation (thiobarbituric acid-reactive substancesformation) in vitro (59 ± 5 vs. 24 ± 4 nmol malondialdehyde/mgprotein; P < 0.001) dependent on functional 12/15-lipoxygenase(12/15-LO). Low density lipoprotein receptor-deficient (LDLR^–/–)mice were transplanted with bone marrow from either sPLA₂ transgenicmice (sPLA₂ $->$ LDLR^–/–; n = 19) or wild-type C57BL/6littermates (C57 BL/6 $->$ LDLR^–/–; n = 19) and maintainedfor 8 weeks on chow and then for 9 weeks on a Western-type diet.Plasma sPLA₂ activity and plasma lipoprotein profiles were notsignificantly different between sPLA₂ $->$ LDLR^–/– andC57BL/6 $->$ LDLR^–/– mice. Aortic root atherosclerosiswas increased by 57% in sPLA₂ $->$ LDLR^–/– mice comparedwith C57BL/6 $->$ LDLR^–/– controls (P < 0.05). Foamcell formation in vitro and in vivo was increased significantly.Urinary, plasma, and aortic levels of the isoprostane 8,12-iso-iPF₂-VIand aortic levels of 12/15-LO reaction products were each significantlyhigher (P < 0.001) in sPLA₂ $->$ LDLR^–/– compared withC57BL/6 $->$ LDLR^–/– mice, indicating significantly increasedin vivo oxidative stress in sPLA₂ $->$ LDLR^–/–. These data demonstrate that macrophage-specific overexpressionof human sPLA₂ increases atherogenesis by directly modulatingfoam cell formation and in vivo oxidative stress without anyeffect on systemic sPLA₂ activity and lipoprotein metabolism. Supplementary key words secretory phospholipase A₂ • lipoxygenase • hypercholesterolemia • inflammation • lipoproteins