title: ERK5 activation in macrophages promotes efferocytosis and inhibits atherosclerosis.
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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Heo
authors.affiliation: 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.).
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Cushman
authors.affiliation: 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.).
authors.forename: Masashi
authors.initials: M
authors.lastname: Akaike
authors.affiliation: 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.).
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Woo
authors.affiliation: 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.).
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.).
authors.forename: Xing
authors.initials: X
authors.lastname: Qiu
authors.affiliation: 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.).
authors.forename: Keigi
authors.initials: K
authors.lastname: Fujiwara
authors.affiliation: 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.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Abe
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D010587:Phagocytosis / Q000502:physiology*
chemical_list: D048054:Mitogen-Activated Protein Kinase 7
keywords: atherosclerosis; signal transduction