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,Janusz H.S Kabarowski

doi:10.1194/jlr.m500085-jlr200

Abstract

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.

Highlights

Lysophosphatidylcholine (LPC) is considered a major proatherogenic component of oxidized low density lipoprotein based on its proinflammatory actions in vitro
Our data show that G2A but not G protein-coupled receptor 4 (GPR4) is expressed in inflammatory cells, whereas GPR4 is the predominant receptor in aortic endothelial cells that express lower levels of G2A
By generating G2A-deficient low density lipoprotein receptor knockout (LDLRϪ/Ϫ) mice and examining how the loss of established G2A-mediated effects of LPC impact atherosclerotic lesion development and morphology, we have directly addressed one aspect of its pathophysiological role in atherosclerosis

Summary

Introduction

Lysophosphatidylcholine (LPC) is considered a major proatherogenic component of oxidized low density lipoprotein based on its proinflammatory actions in vitro. G2A mediates proapoptotic effects of LPC and may 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 G2Adeficient low density lipoprotein receptor knockout mice. 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.—Parks, B. There is no evidence to support a proton-sensing function for murine G2A in addition to its role as an effector of LPC action, and the physiological significance of the weak pH sensitivity of the human receptor is questionable and requires further study

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Results

Conclusion