Macrophage-specific expression of group IIA sPLA2 results in accelerated atherogenesis by increasing oxidative stress

Abstract

Group IIA secretory phospholipase A2 (sPLA2) is an acute-phase protein mediating decreased plasma HDL cholesterol and increased atherosclerosis. This study investigated the impact of macrophage-specific sPLA2 overexpression on lipoprotein metabolism and atherogenesis. Macrophages from sPLA2 transgenic mice have 2.5 times increased rates of LDL oxidation (thiobarbituric acid-reactive substances formation) in vitro (59 ± 5 vs. 24 ± 4 nmol malondialdehyde/mg protein; 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 transgenic mice (sPLA2→ LDLR−/−; n = 19) or wild-type C57BL/6 littermates (C57 BL/6→LDLR−/−; n = 19) and maintained for 8 weeks on chow and then for 9 weeks on a Western-type diet. Plasma sPLA2 activity and plasma lipoprotein profiles were not significantly different between sPLA2→LDLR−/− and C57BL/6→LDLR−/− mice. Aortic root atherosclerosis was increased by 57% in sPLA2→LDLR−/− mice compared with C57BL/6→LDLR−/− controls (P < 0.05). Foam cell formation in vitro and in vivo was increased significantly. Urinary, plasma, and aortic levels of the isoprostane 8,12-iso-iPF2α-VI and aortic levels of 12/15-LO reaction products were each significantly higher (P < 0.001) in sPLA2→LDLR−/− compared with C57BL/6→LDLR−/− mice, indicating significantly increased in vivo oxidative stress in sPLA2→ LDLR−/−.These data demonstrate that macrophage-specific overexpression of human sPLA2 increases atherogenesis by directly modulating foam cell formation and in vivo oxidative stress without any effect on systemic sPLA2 activity and lipoprotein metabolism.

Keywords

• secretory phospholipase A2
• lipoxygenase
• hypercholesterolemia
• inflammation
• lipoproteins