title: Absence of SOCS3 in the cardiomyocyte increases mortality in a gp130-dependent manner accompanied by contractile dysfunction and ventricular arrhythmias.
abstract: BACKGROUND
  Suppressor of cytokine signaling-3 (SOCS3) is a key negative-feedback regulator of the gp130 receptor that provides crucial signaling for cardiac hypertrophy and survival; however, an in vivo role of SOCS3 regulation on cardiac gp130 signaling remains obscure.
  
  
  RESULTS
  We generated cardiac-specific SOCS3 knockout (SOCS3 cKO) mice. These mice showed increased activation of gp130 downstream signaling targets (STAT3, ERK1/2, AKT, and p38) from 15 weeks of age and developed cardiac dysfunction from approximately 25 weeks of age with signs of heart failure. Surprisingly, SOCS3 cKO failing hearts had minimal histological abnormalities with intact myofibril ultrastructure. In addition, Ca(2+) transients were significantly increased in SOCS3 cKO failing hearts compared with wild-type hearts. We also found that Ser23/24 residues of troponin I were hypophosphorylated in SOCS3 cKO hearts before the manifestation of cardiac dysfunction. These data suggested the presence of abnormalities in myofilament Ca(2+) sensitivity in SOCS3 cKO mice. In addition to the contractile dysfunction, we found various ventricular arrhythmias in SOCS3 cKO nonfailing hearts accompanied by a sarcoplasmic reticulum Ca(2+) overload. To determine the contribution of gp130 signaling to the cardiac phenotype that occurs with SOCS3 deficiency, we generated cardiac-specific gp130 and SOCS3 double KO mice. Double KO mice lived significantly longer and had different histological abnormalities when compared with SOCS3 cKO mice, thus demonstrating the importance of gp130 signaling in the SOCS3 cKO cardiac phenotype.
  
  
  CONCLUSIONS
  Our results demonstrate an important role of SOCS3 regulation on cardiac gp130 signaling in the pathogenesis of contractile dysfunction and ventricular arrhythmias.
authors.affiliation: Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA. tyajima@ucsd.edu
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Yajima
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Murofushi
authors.forename: Hanbing
authors.initials: H
authors.lastname: Zhou
authors.forename: Stanley
authors.initials: S
authors.lastname: Park
authors.forename: Jonathan
authors.initials: J
authors.lastname: Housman
authors.forename: Zhao-Hua
authors.initials: ZH
authors.lastname: Zhong
authors.forename: Michinari
authors.initials: M
authors.lastname: Nakamura
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Machida
authors.forename: Kyung-Kuk
authors.initials: KK
authors.lastname: Hwang
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yajima
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Kirk U
authors.initials: KU
authors.lastname: Knowlton
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000401:mortality* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism / Q000401:mortality* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D050796:STAT3 Transcription Factor; C568321:Scn5a protein, mouse; C491411:Socs3 protein, mouse; D015222:Sodium Channels; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050822:Cytokine Receptor gp130; D002118:Calcium
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