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Originally published In Press as doi:10.1194/jlr.M400469-JLR200 on May 16, 2005

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Journal of Lipid Research, Vol. 46, 1604-1614, August 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

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

Uwe J. F. Tietge1,*,{dagger}, Domenico Pratico§, Tao Ding§, Colin D. Funk**, Reeni B. Hildebrand{dagger}{dagger}, Theo Van Berkel{dagger}{dagger} and Miranda Van Eck{dagger}{dagger}

* Department of Medicine, Charité Campus Mitte, Humboldt University, Berlin, Germany
{dagger} Center for Liver, Digestive, and Metabolic Diseases, University of Groningen Medical Center, Groningen, The Netherlands
§ Center for Experimental Therapeutics, Department of Pharmacology, University of Pennsylvania, Philadelphia, PA
** Departments of Physiology and Biochemistry, Queen's University, Kingston, Ontario, Canada
{dagger}{dagger} Division of Biopharmaceutics, Gorlaeus Laboratories, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands

Published, JLR Papers in Press, May 16, 2005. DOI 10.1194/jlr.M400469-JLR200

1 To whom correspondence should be addressed. e-mail: u_tietge{at}yahoo.com

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-iPF2{alpha}-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.

Supplementary key words secretory phospholipase A2 • lipoxygenase • hypercholesterolemia • inflammation • lipoproteins


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