A CD36-dependent signaling cascade is necessary for macrophage foam cell formation.
Accumulation of macrophage foam cells in atherosclerotic blood vessel intima is a critical component of atherogenesis mediated by scavenger receptor-dependent internalization of oxidized LDL. We demonstrated by coimmunoprecipitation and pull-down assays that the macrophage scavenger receptor CD36 associates with a signaling complex containing Lyn and MEKK2. The MAP kinases JNK1 and JNK2 were specifically phosphorylated in macrophages exposed to oxLDL. Using cells isolated from SRA, TLR2, or CD36 null mice, and phospholipid ligands specific for either SRA or CD36, we showed that JNK activation was mediated by CD36. Both foam cell formation and activation of JNK2 in hyperlipidemic mice were diminished in the absence of CD36. Furthermore, inhibition of Src or JNK blocked oxLDL uptake and inhibited foam cell formation in vitro and in vivo. These findings show that a specific CD36-dependent signaling pathway initiated by oxLDL is necessary for foam cell formation and identify potential targets for antiatherosclerosis therapy.
Rahaman
S Ohidar
SO
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Lennon
David J
DJ
Febbraio
Maria
M
Podrez
Evgeny A
EA
Hazen
Stanley L
SL
Silverstein
Roy L
RL
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D018955:CD36 Antigens / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005487:Foam Cells / Q000378:metabolism*; D006949:Hyperlipidemias / Q000378:metabolism* / Q000503:physiopathology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D048730:MAP Kinase Kinase Kinase 2 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018955:CD36 Antigens; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D008077:Lipoproteins, LDL; D048730:MAP Kinase Kinase Kinase 2; D048056:Mitogen-Activated Protein Kinase 9; D051195:Toll-Like Receptor 2; D019061:src-Family Kinases; C493486:Tlr2 protein, mouse; C099252:oxidized low density lipoprotein; C060902:lyn protein-tyrosine kinase; C482619:Map3k2 protein, mouse; C115472:Cyfip1 protein, mouse