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Papers In Press, published online ahead of print April 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800361-JLR200

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Journal of Lipid Research, Vol. 50, 623-629, April 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

The synergistic inhibition of atherogenesis in apoE^–/– mice between pravastatin and the sPLA₂ inhibitor varespladib (A-002)

Zory Shaposhnik^*, Xuping Wang, Joaquim Trias, Heather Fraser and Aldons J. Lusis^1,*,

^* Division of Cardiology, David Geffen School of Medicine at University of California at Los Angeles (UCLA), Los Angeles, CA 90095
Departments of Medicine, Microbiology, Immunology and Molecular Genetics, Department of Human Genetics, and Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA 90095-1679
Anthera Pharmaceuticals, Inc., Hayward, CA 94545

The online version of this article (available at http://www.jlr.org) contains supplementary Methods, Results, and Figures.

Work in the laboratory of A.J.L. was supported by grants HL30568 and HL28481. This work was funded by a grant from Anthera to A.J.L. J.T. and H.F. are employees of and hold stock in Anthera Pharmaceuticals, Inc. A.J.L. has acted as an advisor to Anthera Pharmaceuticals, Inc, but neither Z.S. nor A.J.L. have any financial interest in Anthera.

Published, JLR Papers in Press, November 21, 2008.

¹ To whom correspondence should be addressed. e-mail: jlusis{at}mednet.ucla.edu

Secretory phospholipase A2 (sPLA₂) activity promotes foam cell formation, increases proinflammatory bioactive lipid levels, decreases HDL levels, increases atherosclerosis in transgenic mice, and is an independent marker of cardiovascular disease. The effects of the sPLA₂ inhibitor A-002 (varespladib) and pravastatin as monotherapies and in combination on atherosclerosis, lipids, and paraoxonase (PON) activity in apoE^–/– mice were investigated. Male apoE^–/– mice were placed on a 12-week high-fat diet supplemented with A-002 alone or combined with pravastatin. Atherosclerotic lesions were examined for size and composition using en face analysis, Movat staining, anti-CD68, and anti- actin antibodies. Plasma lipids and PON activity were measured. A-002 decreased atherosclerotic lesion area by 75% while increasing fibrous cap size by over 200%. HDL levels increased 40% and plasma PON activity increased 80%. Pravastatin monotherapy had no effect on lesion size but when combined with A-002, decreased lesion area 50% and total cholesterol levels 18% more than A-002 alone. A-002, a sPLA₂ inhibitor, acts synergistically with pravastatin to decrease atherosclerosis, possibly through decreased levels of systemic inflammation or decreased lipid levels. A-002 treatment also resulted in a profound increase in plasma PON activity and significantly larger fibrous caps, suggesting the formation of more stable plaque architecture.

Supplementary key words drugs • lipoproteins • varespladib • secretory phospholipase A2

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