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J. Lipid Res.
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A more recent version of this article appeared on August 1, 2005

Papers In Press, published online ahead of print May 16, 2005
J. Lipid Res., doi:10.1194/jlr.M400469-JLR200
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Submitted on November 27, 2004
Revised on April 20, 2005
Accepted on May 3, 2005

Macrophage-specific expression of type IIA secretory phospholipase A2 results in accelerated early atherogenesis by increasing oxidative stress in LDL-receptor deficient mice

Uwe J. F. Tietge, Domenico Pratico, Tao Ding, Colin D. Funk, Reeni B. Hildebrand, Theo J. Van Berkel, and Miranda Van Eck

Center for Liver, Digestive and Metabolic Diseases, University of Groningen Medical Center, Groningen 9713 GZ

Corresponding Author: u_tietge{at}yahoo.com

Type IIA secretory phospholipase A2 (sPLA2) is an acute phase protein mediating decreased plasma HDL cholesterol levels and increased atherosclerosis. The aim of this study was to investigate the impact of macrophage-specific sPLA2 overexpression on lipoprotein metabolism and atherogenesis. Macrophages from sPLA2-transgenic mice express functional sPLA2 enzyme and have 2.5-times increased rates of LDL oxidation (TBARS formation) in vitro (59 ± 5 vs. 24 ± 4 nmol MDA/mg protein, resp., p<0.001) that are dependent on functional 12/15-lipoxygenase. LDLR-/- mice were transplanted with bone marrow from either sPLA2-tg mice (sPLA2LDLR-/-, n=19) or wild-type C57BL/6 littermates (C57BL/6LDLR-/-, n=19) and maintained for 8 weeks on chow, then for 9 weeks on Western-type diet. Plasma sPLA2 activity and plasma lipoprotein profiles were not significantly different between sPLA2LDLR-/- and C57BL/6LDLR-/- mice. Aortic root atherosclerosis was 57% increased in sPLA2LDLR-/- compared with C57BL/6LDLR-/- controls (231,415 ± 26,390 vs. 147,211 ± 20,679 mu m2, resp., p<0.05). Foam cell formation in vitro and in vivo was significantly increased. Urinary, plasma and aortic levels of the isoprostane 8,12-iso-iPF2alpha -VI, a specific marker of lipid peroxidation, as well as aortic levels of 12/15-lipoxygenase reaction products were each significantly higher in sPLA2LDLR-/- compared with C57BL/6LDLR-/- controls (p<0.001) indicating a significant increase of in vivo oxidative stress in sPLA2LDLR-/-. These data demonstrate that selective macrophage 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.


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