on September 21, 2006
Published online before print September 21, 2006, doi: 10.1161/01.ATV.0000246774.02426.71
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Submitted on May 17, 2006
Accepted on September 7, 2006
Loss of the Lysophosphatidylcholine Effector, G2A, Ameliorates Aortic Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice
Brian W. Parks ;
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.
* To whom correspondence should be addressed. 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.
Key words: atherosclerosis • chemotaxis • G2A • lysophosphatidylcholine • macrophages
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