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A CD36‐dependent signaling cascade is necessary for macrophage foam cell formation
Author(s) -
Rahaman Shaik Ohidar,
Len David,
Febbraio Maria,
Podrez Eugene,
Hazen Stanley,
Silverstein Roy
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a481-c
Subject(s) - foam cell , cd36 , microbiology and biotechnology , scavenger receptor , chemistry , kinase , macrophage , internalization , lyn , signal transduction , phosphorylation , proto oncogene tyrosine protein kinase src , intracellular , receptor , ligand (biochemistry) , biology , in vitro , biochemistry , lipoprotein , cholesterol
Initiation and progression of atherosclerotic lesions is associated with accumulation of foam cells in vessel wall. A critical step in foam cell formation is recognition and internalization of oxidized low density lipoprotein (oxLDL) by macrophage receptors CD36 and SR‐A. We hypothesized that these ligand/receptor engagements activate specific signaling pathways that influence the atherogenic process. We found intracellular domain of CD36 precipitated a multiprotein complex from monocytic cells containing Lyn and MEKK2. We also found that incubation of macrophages with oxLDL led to phosphorylation of JNK1 and JNK2 in cells isolated from wild type mice and SRA−/ −, but not from CD36−/ −. To confirm CD36 specificity of JNK activation we showed that acetylated LDL, a specific ligand for SRA, did not activate JNK, while NO 2 LDL, a specific ligand for CD36, activated JNKs in wild type but not CD36−/ − macrophages. We demonstrated further that oxLDL upregulated ATF2 and c‐Jun in wild type but not CD36−/− macrophages. By injecting macrophages from WT and CD36−/ − mice into apoE−/ − mice we also found that JNK is specifically activated by in vivo proatherogenic LDL in CD36‐dependent fashion. Importantly, inhibition of Src kinases or JNK activation by inhibitors resulted in reduction of oxLDL uptake by macrophages and dramatic inhibition of in vitro foam cell formation. These studies demonstrate that CD36 associates with a signaling complex containing Src and MAP kinases and that CD36‐dependent activation of JNK by oxLDL is an important regulator of the atherosclerotic process.