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

Group IIA secretory phospholipase A(2) (sPLA(2)) isan acute-phase protein mediating decreased plasma HDL cholesterol and increased atherosclerosis. This study investigated the impact of macrophage-specific sPLA(2) overexpression on lipoprotein metabolism and atherogenesis. Macrophages from sPLA(2) transgenic mice have 2.5 times increased rates of LDL oxidation ( thiobarbituric acid-reactive substances formation) in vitro ( 59 +/- 5 vs. 24 +/- 4 nmol malon-dialdehyde/ 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 sPLA 2 transgenic mice ( sPLA(2)-> 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 sPLA 2 activity and plasma lipoprotein profiles were not significantly different between sPLA(2). LDLR-/- and C57BL/ 6 -> LDLR-/- mice. Aortic root atherosclerosis was increased by 57% in sPLA(2). 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-iPF(2 alpha)-VI and aortic levels of (12/15-LO) reaction products were each significantly higher ( P < 0.001) in sPLA(2) -> LDLR-/- compared with C57BL/6. LDLR-/- mice, indicating significantly increased in vivo oxidative stress in sPLA(2). LDLR-/-.