title: NF2 Activates Hippo Signaling and Promotes Ischemia/Reperfusion Injury in the Heart.
abstract: BACKGROUND
  NF2 (neurofibromin 2) is an established tumor suppressor that promotes apoptosis and inhibits growth in a variety of cell types, yet its function in cardiomyocytes remains largely unknown.
  
  
  OBJECTIVE
  We sought to determine the role of NF2 in cardiomyocyte apoptosis and ischemia/reperfusion (I/R) injury in the heart.
  
  
  RESULTS
  We investigated the function of NF2 in isolated cardiomyocytes and mouse myocardium at baseline and in response to oxidative stress. NF2 was activated in cardiomyocytes subjected to H2O2 and in murine hearts subjected to I/R. Increased NF2 expression promoted the activation of Mst1 (mammalian sterile 20-like kinase 1) and the inhibition of Yap (Yes-associated protein), whereas knockdown of NF2 attenuated these responses after oxidative stress. NF2 increased the apoptosis of cardiomyocytes that appeared dependent on Mst1 activity. Mice deficient for NF2 in cardiomyocytes, NF2 cardiomyocyte-specific knockout (CKO), were protected against global I/R ex vivo and showed improved cardiac functional recovery. Moreover, NF2 cardiomyocyte-specific knockout mice were protected against I/R injury in vivo and showed the upregulation of Yap target gene expression. Mechanistically, we observed nuclear association between NF2 and its activator MYPT-1 (myosin phosphatase target subunit 1) in cardiomyocytes, and a subpopulation of stress-induced nuclear Mst1 was diminished in NF2 CKO hearts. Finally, mice deficient for both NF2 and Yap failed to show protection against I/R indicating that Yap is an important target of NF2 in the adult heart.
  
  
  CONCLUSIONS
  NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through the activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart.
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
authors.forename: Takahisa
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Sciarretta
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
authors.forename: Jae Im
authors.initials: JI
authors.lastname: Jeong
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
authors.forename: Shohei
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Park
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
authors.forename: Chiao-Po
authors.initials: CP
authors.lastname: Hsu
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
authors.forename: Bin
authors.initials: B
authors.lastname: Tian
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
authors.forename: Duojia
authors.initials: D
authors.lastname: Pan
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.). delredo@njms.rutgers.edu.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Del Re
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000090683:Hippo Signaling Pathway; D006861:Hydrogen Peroxide / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D025581:Neurofibromin 2 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D025581:Neurofibromin 2; D006861:Hydrogen Peroxide; D017346:Protein Serine-Threonine Kinases
keywords: apoptosis; cardiomyocyte; neurofibromin 2; oxidative stress; reperfusion injury