Loss of the lysophosphatidylcholine effector, G2A, ameliorates aortic atherosclerosis in low-density lipoprotein receptor knockout mice

Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2703-9. doi: 10.1161/01.ATV.0000246774.02426.71. Epub 2006 Sep 21.

Abstract

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).

Conclusions: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cholesterol, HDL / blood
  • Cholesterol, HDL / metabolism
  • Disease Progression
  • Female
  • Gene Expression Regulation / genetics
  • Hypercholesterolemia / physiopathology
  • Lysophosphatidylcholines / metabolism*
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Sinus of Valsalva / metabolism
  • Sinus of Valsalva / pathology
  • Tunica Intima / pathology

Substances

  • Cell Cycle Proteins
  • Cholesterol, HDL
  • G2A receptor
  • Lysophosphatidylcholines
  • Receptors, G-Protein-Coupled
  • Receptors, LDL