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Journal of Lipid Research, Vol. 46, 1405-1415, July 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Loss of G2A promotes macrophage accumulation in atherosclerotic lesions of low density lipoprotein receptor-deficient mice

Brian W. Parks^*, Ginger P. Gambill^*, Aldons J. Lusis and Janusz H. S. Kabarowski^1,*

^* Department of Microbiology, University of Alabama, Birmingham, AL 35294-2170
Department of Medicine, University of California, Los Angeles, CA 90095-1679

Published, JLR Papers in Press, April 16, 2005. DOI 10.1194/jlr.M500085-JLR200

¹ To whom correspondence should be addressed. e-mail: janusz{at}uab.edu

Lysophosphatidylcholine (LPC) is considered a major proatherogenic component of oxidized low density lipoprotein based on its proinflammatory actions in vitro. LPC stimulates macrophage and T-cell chemotaxis via the G protein-coupled receptor G2A and may thus promote inflammatory cell infiltration during atherosclerotic lesion development. However, G2A also mediates proapoptotic effects of LPC and may therefore promote the death of inflammatory cells within developing lesions. To determine how these effects of LPC modify atherogenesis, we examined atherosclerotic lesion development in G2A-sufficient and G2A-deficient low density lipoprotein receptor knockout mice. Although LPC species capable of activating G2A-dependent responses were increased during lesion development, G2A-deficient mice developed lesions similar in size to those in their G2A-sufficient counterparts. Loss of G2A during atherosclerotic lesion development did not reduce macrophage and T-cell infiltration but instead resulted in increased lesional macrophage content associated with reduced numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeled cells and decreased collagen deposition.

These data indicate that the ability of LPC to stimulate macrophage and T-cell chemotaxis via G2A is not manifested in vivo and that G2A-mediated proapoptotic rather than chemotactic action is most penetrant during atherogenesis and may modify the stability of atherosclerotic lesions by promoting macrophage death.

Abbreviations: ESI-MS/MS, electrospray ionization-tandem mass spectrometry; FCS, fetal calf serum; GPCR, G protein-coupled receptor; GPR4, G protein-coupled receptor 4; LDLR^–/–, low density lipoprotein receptor knockout; LPC, lysophosphatidylcholine; MPO, myeloperoxidase; OGR1, ovarian cancer G protein-coupled receptor 1; OxLDL, oxidized low density lipoprotein; PAF-AH, platelet-activating factor-acetylhydrolase; TDAG8, T-cell death-associated gene 8; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling

Supplementary key words atherosclerosis • lysophosphatidylcholine • T cells • chemotaxis • apoptosis

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