Oxidized LDL-mediated macrophage survival involves elongation factor-2 kinase.
OBJECTIVE
Macrophage survival and proliferation is believed to be a contributing factor in the development of early atherosclerotic lesions. Oxidized low density lipoprotein (oxLDL), a key mediator in the pathogenesis of this disease, has been shown to block apoptosis in macrophages deprived of growth factor. In this report, we investigate the mechanism of oxLDL-mediated macrophage survival.


RESULTS
OxLDL, but not native LDL (nLDL), induces an immediate and oscillatory increase in intracellular calcium ([Ca(2+)](i)). We also show that the calcium/calmodulin dependent kinase, eukaryotic elongation factor-2 kinase (eEF2 kinase), is activated in response to oxLDL, an effect that can be blocked by inhibiting calcium mobilization. Furthermore, selective inhibition of eEF2 kinase reverses the prosurvival effect of oxLDL and results in cellular apoptosis. p38 MAP kinase, a negative regulator of eEF2 kinase, is activated on growth factor withdrawal, a response that can be inhibited by oxLDL. Finally, we show that oxLDL, by activating eEF2 kinase, phosphorylates and therefore inhibits eEF2, resulting in an overall decrease in protein synthesis.


CONCLUSIONS
These results indicate a novel signaling pathway in which oxLDL can block macrophage apoptosis by mobilizing calcium and activating eEF2 kinase.
Chen
Johnny H
JH
Department of Medicine, University of British Columbia, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada.
Riazy
Maziar
M
Smith
Ewan M
EM
Proud
Christopher G
CG
Steinbrecher
Urs P
UP
Duronio
Vincent
V
D000818:Animals; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002118:Calcium / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology; D054736:Elongation Factor 2 Kinase / Q000302:isolation & purification / Q000378:metabolism*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology; D008077:Lipoproteins, LDL / Q000502:physiology*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D009195:Peroxidase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002518:Ceramides; D018841:HSP90 Heat-Shock Proteins; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D009195:Peroxidase; D054736:Elongation Factor 2 Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium