ERK5 Activation in Macrophages Promotes Efferocytosis and Inhibits Atherosclerosis

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. When macrophages were fed apoptotic cells or treated with pitavastatin...

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Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 2014-07, Vol.130 (2), p.180-191
Main Authors: HEO, Kyung-Sun, CUSHMAN, Hannah J, AKAIKE, Masashi, WOO, Chang-Hoon, XIN WANG, XING QIU, FUJIWARA, Keigi, ABE, Jun-Ichi
Format: Article
Language:English
Subjects:
Animals
Atherosclerosis (general aspects, experimental research)
Atherosclerosis - enzymology
Atherosclerosis - pathology
Atherosclerosis - prevention & control
Biological and medical sciences
Blood and lymphatic vessels
Cardiology. Vascular system
Cells, Cultured
Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous
Enzyme Activation - physiology
Macrophages - enzymology
Macrophages - pathology
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitogen-Activated Protein Kinase 7 - metabolism
Phagocytosis - physiology
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Summary: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. 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. 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.
ISSN:0009-7322
1524-4539
DOI:10.1161/circulationaha.113.005991