Kyung-Sun Heo1, Hannah J Cushman2, Masashi Akaike2, Chang-Hoon Woo2, Xin Wang2, Xing Qiu2, Keigi Fujiwara2, Jun-ichi Abe1. 1. From the Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY (K.H., H.J.C., C.W., K.F., J.A.); Department of Medical Education, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto-cho, Tokushima, Japan (M.A.); Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom (X.W.); and Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY (X.Q.). Kyung-Sun_Heo@urmc.rochester.edu Jun-ichi_Abe@urmc.rochester.edu. 2. From the Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY (K.H., H.J.C., C.W., K.F., J.A.); Department of Medical Education, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto-cho, Tokushima, Japan (M.A.); Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom (X.W.); and Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY (X.Q.).
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.
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.
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