title: Muscle-specific RING finger 1 negatively regulates pathological cardiac hypertrophy through downregulation of calcineurin A.
abstract: BACKGROUND
  Muscle-specific RING finger protein-1 (MuRF1) is an E3 ligase that inhibits cardiac hypertrophy. However, how MuRF1 regulates cardiac hypertrophy and function during pressure overload (PO) remains poorly understood. We investigated the role of endogenous MuRF1 in regulating cardiac hypertrophy in response to PO in vivo.
  
  
  RESULTS
  Transverse aortic constriction (TAC) for 4 weeks significantly reduced expression of MuRF1 in the mouse heart. After 2 and 4 weeks of TAC, MuRF1 knockout (Murf1(-/-)) mice exhibited enhanced cardiac hypertrophy and left ventricular (LV) dysfunction compared with that of nontransgenic (NTg) mice. Histological analyses showed that Murf1(-/-) mice exhibited more severe fibrosis and apoptosis than NTg mice after TAC. TAC-induced increases in the activity of a nuclear factor of activated T cells (NFAT) luciferase reporter were significantly greater in Murf1(-/-) than in NTg mice. TAC-induced increases in calcineurin A (CnA) expression were also significantly enhanced in Murf1(-/-) compared with that in NTg mice. Coimmunoprecipitation assays showed that endogenous MuRF1 and CnA interact with one another. Polyubiquitination of CnA was attenuated in Murf1(-/-) mouse hearts at baseline and in response to TAC, and the protein stability of CnA was enhanced in cardiomyocytes, in which MuRF1 was downregulated in vitro. Furthermore, MuRF1 directly ubiquitinated CnA in vitro. Cardiac-specific overexpression of ZAKI-4β, an endogenous inhibitor of CnA, significantly suppressed the enhancement of TAC-induced cardiac hypertrophy and dysfunction, as well as increases in cardiac fibrosis and apoptosis, in Murf1(-/-) mice.
  
  
  CONCLUSIONS
  Endogenous MuRF1 negatively regulates cardiac hypertrophy and dysfunction in response to PO through inhibition of the calcineurin-NFAT pathway.
authors: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ (Y.M., S.U., P.Z., D.Z., J.S.); Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan (S.U., M.T., S.K.); Department of Genome Science, School of Dentistry, Aichi-Gakuin University, Nagoya, Aichi, Japan (M.Y.); and Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan (Y.M., M.I.).
authors: Yasuhiro
authors: Y
authors: Maejima
authors: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ (Y.M., S.U., P.Z., D.Z., J.S.); Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan (S.U., M.T., S.K.); Department of Genome Science, School of Dentistry, Aichi-Gakuin University, Nagoya, Aichi, Japan (M.Y.); and Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan (Y.M., M.I.).
authors: Soichiro
authors: S
authors: Usui
authors: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ (Y.M., S.U., P.Z., D.Z., J.S.); Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan (S.U., M.T., S.K.); Department of Genome Science, School of Dentistry, Aichi-Gakuin University, Nagoya, Aichi, Japan (M.Y.); and Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan (Y.M., M.I.).
authors: Peiyong
authors: P
authors: Zhai
authors: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ (Y.M., S.U., P.Z., D.Z., J.S.); Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan (S.U., M.T., S.K.); Department of Genome Science, School of Dentistry, Aichi-Gakuin University, Nagoya, Aichi, Japan (M.Y.); and Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan (Y.M., M.I.).
authors: Masayuki
authors: M
authors: Takamura
authors: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ (Y.M., S.U., P.Z., D.Z., J.S.); Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan (S.U., M.T., S.K.); Department of Genome Science, School of Dentistry, Aichi-Gakuin University, Nagoya, Aichi, Japan (M.Y.); and Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan (Y.M., M.I.).
authors: Shuichi
authors: S
authors: Kaneko
authors: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ (Y.M., S.U., P.Z., D.Z., J.S.); Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan (S.U., M.T., S.K.); Department of Genome Science, School of Dentistry, Aichi-Gakuin University, Nagoya, Aichi, Japan (M.Y.); and Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan (Y.M., M.I.).
authors: Daniela
authors: D
authors: Zablocki
authors: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ (Y.M., S.U., P.Z., D.Z., J.S.); Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan (S.U., M.T., S.K.); Department of Genome Science, School of Dentistry, Aichi-Gakuin University, Nagoya, Aichi, Japan (M.Y.); and Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan (Y.M., M.I.).
authors: Mitsuhiro
authors: M
authors: Yokota
authors: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ (Y.M., S.U., P.Z., D.Z., J.S.); Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan (S.U., M.T., S.K.); Department of Genome Science, School of Dentistry, Aichi-Gakuin University, Nagoya, Aichi, Japan (M.Y.); and Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan (Y.M., M.I.).
authors: Mitsuaki
authors: M
authors: Isobe
authors: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ (Y.M., S.U., P.Z., D.Z., J.S.); Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan (S.U., M.T., S.K.); Department of Genome Science, School of Dentistry, Aichi-Gakuin University, Nagoya, Aichi, Japan (M.Y.); and Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan (Y.M., M.I.). sadoshju@njms.rutgers.edu.
authors: Junichi
authors: J
authors: Sadoshima
mesh_terms: D000818:Animals; D001011:Aorta / Q000503:physiopathology; D019703:Calcineurin / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D000070584:Tripartite Motif Proteins; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D019703:Calcineurin
keywords: calcineurin; cardiomegaly; muscular atrophy; ubiquitin protein ligases; ubiquitination