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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2703.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Loss of the Lysophosphatidylcholine Effector, G2A, Ameliorates Aortic Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice

Brian W. Parks; Aldons J. Lusis; Janusz H.S. Kabarowski

From the Department of Microbiology (B.W.P., J.H.S.K.), University of Alabama at Birmingham, Ala; and the Department of Medicine (A.J.L.), University of California, Los Angeles, Calif.

Correspondence to Dr Janusz H. S. Kabarowski, Department of Microbiology, University of Alabama at Birmingham, BBRB 334, 19th St S, Birmingham, AL 35294-2170. E-mail janusz{at}uab.edu

Objective— Lysophosphatidylcholine is a major product of low-density lipoprotein (LDL) oxidation and secretory phospholipase A₂-mediated lipid hydrolysis within atherosclerotic lesions. The G2A receptor mediates chemotaxis of cultured macrophages and T cells to lysophosphatidylcholine, supporting a pro-atherogenic role for this receptor in vivo. We investigated the ability of G2A to modulate atherosclerosis in mice.

Methods and Results— We measured atherosclerosis in G2A^+/+ and G2A^–/– LDL receptor knockout (LDLR^–/–) mice. Consistent with a previous study, early lesion size at the aortic sinus was unaffected by G2A deficiency. However, G2A deficiency attenuated lesion progression at this site (42% to 44% reduction in average lesion area) and led to robust suppression of atherosclerosis throughout the aorta after short and extended periods of diet intervention (reduction in aortic lesion coverage: 62% to 73% at 9 weeks, 75% to 84% at 20 weeks). In G2A^–/–LDLR^–/– mice, intimal macrophage accumulation at lesion-prone sites of the aorta was significantly reduced in the absence of any detectable effect on T cell recruitment. Examination of lipoprotein profiles revealed elevated levels of circulating high-density lipoprotein (HDL) cholesterol in G2A^–/–LDLR^–/– mice compared with their G2A^+/+LDLR^–/– counterparts after extended periods of diet intervention (54% increase in mean HDL cholesterol concentration).

Conclusion— G2A provides a pro-atherogenic stimulus in vivo consistent with its chemotactic action but to which a pleiotropy of effects, including modulation of lipoprotein metabolism, may also contribute.

The G2A receptor mediates chemotactic and apoptotic effects of lysophosphatidylcholine in vitro. Loss of G2A suppressed aortic atherosclerosis, reduced macrophage accumulation at lesion-prone sites of the aorta, and elevated circulating HDL cholesterol levels in LDLR knockout mice. A pleiotropy of effects may contribute to the pro-atherogenic action of G2A.

Key Words: atherosclerosis • chemotaxis • G2A • lysophosphatidylcholine • macrophages

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