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Publication
Macrophage EP4 deficiency increases apoptosis and suppresses early
atherosclerosis.
Authors Babaev VR, Chew JD, Ding L, Davis S, Breyer MD, Breyer RM, Oates JA, Fazio S,
Linton MF
Submitted By Submitted Externally on 2/12/2009
Status Published
Journal Cell Metabolism
Year 2008
Date Published
Volume : Pages 8(6) : 492 - 501
PubMed Reference 19041765
Abstract Prostaglandin (PG) E(2), a major product of activated macrophages, has been
implicated in atherosclerosis and plaque rupture. The PGE(2) receptors, EP2 and
EP4, are expressed in atherosclerotic lesions and are known to inhibit apoptosis
in cancer cells. To examine the roles of macrophage EP4 and EP2 in apoptosis and
early atherosclerosis, fetal liver cell transplantation was used to generate
LDLR(-/-) mice chimeric for EP2(-/-) or EP4(-/-) hematopoietic cells. After 8
weeks on a Western diet, EP4(-/-) --> LDLR(-/-) mice, but not EP2(-/-) -->
LDLR(-/-) mice, had significantly reduced aortic atherosclerosis with increased
apoptotic cells in the lesions. EP4(-/-) peritoneal macrophages had increased
sensitivity to proapoptotic stimuli, including palmitic acid and free
cholesterol loading, which was accompanied by suppression of activity of p-Akt,
p-Bad, and NF-kappaB-regulated genes. Thus, EP4 deficiency inhibits the PI3K/Akt
and NF-kappaB pathways compromising macrophage survival and suppressing early
atherosclerosis, identifying macrophage EP4-signaling pathways as molecular
targets for modulating the development of atherosclerosis.




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