title: Vav family Rho guanine nucleotide exchange factors regulate CD36-mediated macrophage foam cell formation.
abstract: Lipid-laden macrophages or "foam cells" are the primary components of the fatty streak, the earliest atherosclerotic lesion. Although Vav family guanine nucleotide exchange factors impact processes highly relevant to atherogenesis and are involved in pathways common to scavenger receptor CD36 signaling, their role in CD36-dependent macrophage foam cell formation remains unknown. The goal of the present study was to determine the contribution of Vav proteins to CD36-dependent foam cell formation and to identify the mechanisms by which Vavs participate in the process. We found that CD36 contributes to activation of Vav-1, -2, and -3 in aortae from hyperlipidemic mice and that oxidatively modified LDL (oxLDL) induces activation of macrophage Vav in vitro in a CD36 and Src family kinase-dependent manner. CD36-dependent uptake of oxLDL in vitro and foam cell formation in vitro and in vivo was significantly reduced in Vav null macrophages. These studies for the first time link CD36 and Vavs in a signaling pathway required for macrophage foam cell formation.
authors.affiliation: Department of Cell Biology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA. rahamao@ccf.org
authors.forename: S Ohidar
authors.initials: SO
authors.lastname: Rahaman
authors.forename: Wojciech
authors.initials: W
authors.lastname: Swat
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: Roy L
authors.initials: RL
authors.lastname: Silverstein
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005487:Foam Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D006949:Hyperlipidemias / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008077:Lipoproteins, LDL / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism*; D014657:Vasculitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D051567:Proto-Oncogene Proteins c-vav; C496619:Vav1 protein, mouse; C490565:Vav2 protein, mouse; C496622:Vav3 protein, mouse; C099252:oxidized low density lipoprotein