Macrophage EP4 Deficiency Increases Apoptosis and Suppresses Early Atherosclerosis

Vladimir R. Babaev, Joshua D. Chew, Lei Ding, Sarah Davis, Matthew D. Breyer, Richard M. Breyer, John A. Oates, Sergio Fazio, MacRae F. Linton

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Prostaglandin (PG) E2, a major product of activated macrophages, has been implicated in atherosclerosis and plaque rupture. The PGE2 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-κB-regulated genes. Thus, EP4 deficiency inhibits the PI3K/Akt and NF-κB pathways compromising macrophage survival and suppressing early atherosclerosis, identifying macrophage EP4-signaling pathways as molecular targets for modulating the development of atherosclerosis.

Original languageEnglish (US)
Pages (from-to)492-501
Number of pages10
JournalCell Metabolism
Volume8
Issue number6
DOIs
StatePublished - Dec 6 2008
Externally publishedYes

Fingerprint

Atherosclerosis
Macrophages
Apoptosis
Prostaglandin E Receptors
Palmitic Acid
Cell Transplantation
Peritoneal Macrophages
Phosphatidylinositol 3-Kinases
Dinoprostone
Liver Transplantation
Rupture
Cholesterol
Genes
Neoplasms

Keywords

  • HUMDISEASE
  • SIGNALING

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Babaev, V. R., Chew, J. D., Ding, L., Davis, S., Breyer, M. D., Breyer, R. M., ... Linton, M. F. (2008). Macrophage EP4 Deficiency Increases Apoptosis and Suppresses Early Atherosclerosis. Cell Metabolism, 8(6), 492-501. https://doi.org/10.1016/j.cmet.2008.09.005

Macrophage EP4 Deficiency Increases Apoptosis and Suppresses Early Atherosclerosis. / Babaev, Vladimir R.; Chew, Joshua D.; Ding, Lei; Davis, Sarah; Breyer, Matthew D.; Breyer, Richard M.; Oates, John A.; Fazio, Sergio; Linton, MacRae F.

In: Cell Metabolism, Vol. 8, No. 6, 06.12.2008, p. 492-501.

Research output: Contribution to journalArticle

Babaev, VR, Chew, JD, Ding, L, Davis, S, Breyer, MD, Breyer, RM, Oates, JA, Fazio, S & Linton, MF 2008, 'Macrophage EP4 Deficiency Increases Apoptosis and Suppresses Early Atherosclerosis', Cell Metabolism, vol. 8, no. 6, pp. 492-501. https://doi.org/10.1016/j.cmet.2008.09.005
Babaev VR, Chew JD, Ding L, Davis S, Breyer MD, Breyer RM et al. Macrophage EP4 Deficiency Increases Apoptosis and Suppresses Early Atherosclerosis. Cell Metabolism. 2008 Dec 6;8(6):492-501. https://doi.org/10.1016/j.cmet.2008.09.005
Babaev, Vladimir R. ; Chew, Joshua D. ; Ding, Lei ; Davis, Sarah ; Breyer, Matthew D. ; Breyer, Richard M. ; Oates, John A. ; Fazio, Sergio ; Linton, MacRae F. / Macrophage EP4 Deficiency Increases Apoptosis and Suppresses Early Atherosclerosis. In: Cell Metabolism. 2008 ; Vol. 8, No. 6. pp. 492-501.
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