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Oxidized LDL-Mediated Macrophage Survival Involves Elongation Factor-2 Kinase

Oxidized LDL-Mediated Macrophage Survival Involves Elongation Factor-2 Kinase
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.

Methods and Results— OxLDL, but not native LDL (nLDL), induces an immediate and oscillatory increase in intracellular calcium ([Ca2+]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.

Conclusion— These results indicate a novel signaling pathway in which oxLDL can block macrophage apoptosis by mobilizing calcium and activating eEF2 kinase
oxidized LDL, eEF2 kinase, macrophage, apoptosis, calcium
1079-5642
92
Chen, J. H.
20e582b9-a8b1-4fe4-96f5-631cf9bc5ced
Riazy, M.
6bd5afa5-7def-4554-9655-0635696857ea
Smith, E. M.
a6c44903-825c-4018-84cd-3ca748ab6b68
Proud, C.G.
c2cc50f9-4565-4d59-9dfc-aa70b9268a6e
Steinbrecher, U. P.
8e846db3-4241-4bc6-a160-59e7ea9eecba
Duronio, V.
d91f9636-fbbb-44b5-bcb3-121e56f2cdba
Chen, J. H.
20e582b9-a8b1-4fe4-96f5-631cf9bc5ced
Riazy, M.
6bd5afa5-7def-4554-9655-0635696857ea
Smith, E. M.
a6c44903-825c-4018-84cd-3ca748ab6b68
Proud, C.G.
c2cc50f9-4565-4d59-9dfc-aa70b9268a6e
Steinbrecher, U. P.
8e846db3-4241-4bc6-a160-59e7ea9eecba
Duronio, V.
d91f9636-fbbb-44b5-bcb3-121e56f2cdba

Chen, J. H., Riazy, M., Smith, E. M., Proud, C.G., Steinbrecher, U. P. and Duronio, V. (2009) Oxidized LDL-Mediated Macrophage Survival Involves Elongation Factor-2 Kinase. Arteriosclerosis, Thrombosis, and Vascular Biology, 29 (1), 92. (doi:10.1161/ATVBAHA.108.174599).

Record type: Article

Abstract

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.

Methods and Results— OxLDL, but not native LDL (nLDL), induces an immediate and oscillatory increase in intracellular calcium ([Ca2+]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.

Conclusion— These results indicate a novel signaling pathway in which oxLDL can block macrophage apoptosis by mobilizing calcium and activating eEF2 kinase

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More information

Published date: January 2009
Keywords: oxidized LDL, eEF2 kinase, macrophage, apoptosis, calcium

Identifiers

Local EPrints ID: 142719
URI: https://eprints.soton.ac.uk/id/eprint/142719
ISSN: 1079-5642
PURE UUID: be2c79c8-e86a-4c7a-8d4b-db8ef8d1184e

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Date deposited: 01 Apr 2010 15:56
Last modified: 18 Jul 2017 23:11

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