title: Hippo signaling impedes adult heart regeneration.
abstract: Heart failure due to cardiomyocyte loss after ischemic heart disease is the leading cause of death in the United States in large part because heart muscle regenerates poorly. The endogenous mechanisms preventing mammalian cardiomyocyte regeneration are poorly understood. Hippo signaling, an ancient organ size control pathway, is a kinase cascade that inhibits developing cardiomyocyte proliferation but it has not been studied postnatally or in fully mature adult cardiomyocytes. Here, we investigated Hippo signaling in adult cardiomyocyte renewal and regeneration. We found that unstressed Hippo-deficient adult mouse cardiomyocytes re-enter the cell cycle and undergo cytokinesis. Moreover, Hippo deficiency enhances cardiomyocyte regeneration with functional recovery after adult myocardial infarction as well as after postnatal day eight (P8) cardiac apex resection and P8 myocardial infarction. In damaged hearts, Hippo mutant cardiomyocytes also have elevated proliferation. Our findings reveal that Hippo signaling is an endogenous repressor of adult cardiomyocyte renewal and regeneration. Targeting the Hippo pathway in human disease might be beneficial for the treatment of heart disease.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Heallen
authors.forename: Yuka
authors.initials: Y
authors.lastname: Morikawa
authors.forename: John
authors.initials: J
authors.lastname: Leach
authors.forename: Ge
authors.initials: G
authors.lastname: Tao
authors.forename: James T
authors.initials: JT
authors.lastname: Willerson
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
authors.forename: James F
authors.initials: JF
authors.lastname: Martin
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D006321:Heart / Q000502:physiology*; D000090683:Hippo Signaling Pathway; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D012038:Regeneration / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D034741:RNA, Small Interfering; D017346:Protein Serine-Threonine Kinases
keywords: Cell cycle; Mouse; Proliferation; Regeneration