Macrophage EP4 deficiency increases apoptosis and suppresses early atherosclerosis.
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.
Babaev
Vladimir R
VR
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6300, USA. vladimir.babaev@vanderbilt.edu
Chew
Joshua D
JD
Ding
Lei
L
Davis
Sarah
S
Breyer
Matthew D
MD
Breyer
Richard M
RM
Oates
John A
JA
Fazio
Sergio
S
Linton
Macrae F
MF
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; C487978:Pik3ap1 protein, mouse; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051057:Proto-Oncogene Proteins c-akt