title: G2A deficiency in mice promotes macrophage activation and atherosclerosis.
abstract: G2A is a stress-inducible G protein-coupled receptor that is expressed on several cell types within atherosclerotic lesions. We demonstrated previously that G2A deficiency in mice increased aortic monocyte recruitment and increased monocyte:endothelial interactions. To investigate the impact of G2A deficiency in macrophages, we isolated peritoneal macrophages from G2A(+/+)ApoE(-/-) and G2A(-/-)ApoE(-/-) mice. G2A(-/-)ApoE(-/-) macrophages had significantly lower apoptosis than control macrophages. The prosurvival genes BCL-2, BCL-xL, and cFLIP were increased in G2A(-/-)ApoE(-/-) macrophages. Macrophages from G2A(-/-)ApoE(-/-) mice also had increased proinflammatory status that was indicative of a M1 macrophage phenotype. This was indicated by significantly increased nuclear translocation of nuclear factor kappaB, as well as production of interleukin-12p40, tumor necrosis factor alpha, and interleukin-6, and reduced expression of arginase-I. Moreover, G2A(-/-)ApoE(-/-) macrophages had reduced ability to engulf apoptotic cells in vitro. We examined atherosclerosis in mice fed a Western diet for 10 weeks and found that G2A deficiency increased lesion size in the aortic root by 50%. Plasma lipid levels were not changed in G2A(-/-)ApoE(-/-) mice. However, we found that absence of G2A increased the number of aortic macrophages and attenuated apoptosis in this cell type. Moreover, bone marrow transplantation studies indicated that deficiency of G2A in marrow-derived cells significantly contributed to atherosclerosis development. In the absence of G2A, increased macrophage activation and decreased apoptosis is associated with accumulation of macrophages in the aorta and increased atherosclerosis.
authors.affiliation: Cardiovascular Research Center, University of Charlottesville, Charlottesville, Virginia 22908, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Bolick
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Skaflen
authors.forename: Laura E
authors.initials: LE
authors.lastname: Johnson
authors.forename: Seong-Chun
authors.initials: SC
authors.lastname: Kwon
authors.forename: Deborah
authors.initials: D
authors.lastname: Howatt
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Hedrick
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000276:immunology / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis / Q000276:immunology; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology; D001854:Bone Marrow Cells / Q000502:physiology; D016026:Bone Marrow Transplantation; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000276:immunology*; D016207:Cytokines / Q000097:blood; D015870:Gene Expression / Q000276:immunology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000276:immunology*; D014657:Vasculitis / Q000276:immunology* / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D018797:Cell Cycle Proteins; D016207:Cytokines; C115270:G2A receptor; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; C099252:oxidized low density lipoprotein