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PMID: 16950138 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

A CD36-dependent signaling cascade is necessary for macrophage foam cell formation.

Cell metabolism ·Vol. 4 ·No. 3 ·2006-09-00 ·Pages 211-21

Rahaman SO, Lennon DJ, Febbraio M, Podrez EA, Hazen SL, Silverstein RL

Abstract

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/metabolism Animals Atherosclerosis/drug therapy,metabolism,physiopathology CD36 Antigens/metabolism Endothelial Cells/metabolism Enzyme Inhibitors/pharmacology Female Foam Cells/metabolism Hyperlipidemias/metabolism,physiopathology Hypolipidemic Agents/pharmacology Lipoproteins, LDL/metabolism MAP Kinase Kinase Kinase 2/metabolism Macrophages/metabolism Male Mice Mice, Knockout Mitogen-Activated Protein Kinase 9/antagonists & inhibitors,metabolism Oxidation-Reduction Phosphorylation Signal Transduction/physiology Toll-Like Receptor 2/metabolism src-Family Kinases/antagonists & inhibitors,metabolism
Chemicals
Adaptor Proteins, Signal Transducing CD36 Antigens Enzyme Inhibitors Hypolipidemic Agents Lipoproteins, LDL Sra-1 protein, mouse Tlr2 protein, mouse Toll-Like Receptor 2 oxidized low density lipoprotein Mitogen-Activated Protein Kinase 9 lyn protein-tyrosine kinase src-Family Kinases MAP Kinase Kinase Kinase 2 Map3k2 protein, mouse
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Rahaman S Ohidar
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Lennon David J
Febbraio Maria
Podrez Evgeny A
Hazen Stanley L
Silverstein Roy L
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Article Info
Journal
Cell metabolism
Abbr.
Cell Metab
ISSN
1550-4131
DOI
10.1016/j.cmet.2006.06.007
Published
2006-09-00
Pages
211-21
Language
English
Region
United States
NLM ID
101233170
PMCID
PMC1855263
Subset
IM
Grants
NHLBI NIH HHS · P01 HL046403 · United States
NHLBI NIH HHS · R01 HL070621 · United States
NHLBI NIH HHS · P01 HL072942 · United States
NHLBI NIH HHS · R01 HL070083 · United States
NHLBI NIH HHS · R01 HL70621 · United States
External Links
PubMed source DOI: 10.1016/j.cmet.2006.06.007 PMC Full Text View journal details
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