ERK5 activation in macrophages promotes efferocytosis and inhibits atherosclerosis

Kyung-Sun Heo, Hannah J. Cushman, Masashi Akaike, Chang-Hoon Woo, Xin Wang, Keigi Fujiwara, Jun-ichi Abe

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Background—Efferocytosis is a process by which dead and dying cells are removed by phagocytic cells. Efferocytosis by macrophages is thought to curb the progression of atherosclerosis, but the mechanistic insight of this process is lacking.

    Methods and Results—When macrophages were fed apoptotic cells or treated with pitavastatin in vitro, efferocytosis-related signaling and phagocytic capacity were upregulated in an ERK5 activity–dependent manner. Macrophages isolated from macrophage-specific ERK5-null mice exhibited reduced efferocytosis and levels of gene and protein expression of efferocytosis-related molecules. When these mice were crossed with low-density lipoprotein receptor−/− mice and fed a high-cholesterol diet, atherosclerotic plaque formation was accelerated, and the plaques had more advanced and vulnerable morphology.

    Conclusions—Our results demonstrate that ERK5, which is robustly activated by statins, is a hub molecule that upregulates macrophage efferocytosis, thereby suppressing atherosclerotic plaque formation. Molecules that upregulate ERK5 and its signaling in macrophages may be good drug targets for suppressing cardiovascular diseases.
    Original languageEnglish
    Pages (from-to)180-189
    Number of pages9
    JournalCirculation (Baltimore)
    Volume130
    Issue number2
    DOIs
    Publication statusPublished - Jul 2014

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