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

    74 Scopus citations

    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

    Keywords

    • HUMDISEASE
    • SIGNALING

    ASJC Scopus subject areas

    • Physiology
    • Molecular Biology
    • Cell Biology

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  • Cite this

    Babaev, V. R., Chew, J. D., Ding, L., Davis, S., Breyer, M. D., Breyer, R. M., Oates, J. A., Fazio, S., & 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