Format

Send to

Choose Destination
Cell Metab. 2008 Dec;8(6):492-501. doi: 10.1016/j.cmet.2008.09.005.

Macrophage EP4 deficiency increases apoptosis and suppresses early atherosclerosis.

Author information

1
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6300, USA. vladimir.babaev@vanderbilt.edu

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.

PMID:
19041765
PMCID:
PMC2614698
DOI:
10.1016/j.cmet.2008.09.005
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Publication type

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center