Document Detail


Absence of SOCS3 in the cardiomyocyte increases mortality in a gp130-dependent manner accompanied by contractile dysfunction and ventricular arrhythmias.
MedLine Citation:
PMID:  22082679     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
METHODS AND 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:
Toshitaka Yajima; Yoshiteru Murofushi; Hanbing Zhou; Stanley Park; Jonathan Housman; Zhao-Hua Zhong; Michinari Nakamura; Mitsuyo Machida; Kyung-Kuk Hwang; Yusu Gu; Nancy D Dalton; Tomoko Yajima; Hideo Yasukawa; Kirk L Peterson; Kirk U Knowlton
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-11-14
Journal Detail:
Title:  Circulation     Volume:  124     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-13     Completed Date:  2012-02-07     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2690-701     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Arrhythmias, Cardiac / metabolism,  mortality*,  physiopathology
Calcium / metabolism
Calcium Signaling / physiology
Cardiomyopathy, Dilated / metabolism,  mortality,  physiopathology
Cytokine Receptor gp130 / metabolism*
Disease Models, Animal
Heart Failure / metabolism,  mortality*,  physiopathology
Mice
Mice, Knockout
Myocardial Contraction / physiology*
Myocytes, Cardiac / metabolism*
NAV1.5 Voltage-Gated Sodium Channel
STAT3 Transcription Factor / metabolism
Sodium Channels / metabolism
Suppressor of Cytokine Signaling Proteins / deficiency*,  genetics
Grant Support
ID/Acronym/Agency:
5P01HL046345/HL/NHLBI NIH HHS; 5R01HL092116/HL/NHLBI NIH HHS; R01 HL092116/HL/NHLBI NIH HHS; R01 HL092116-01A2/HL/NHLBI NIH HHS; R01 HL092116-02/HL/NHLBI NIH HHS; R01 HL092116-03/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/NAV1.5 Voltage-Gated Sodium Channel; 0/STAT3 Transcription Factor; 0/Scn5a protein, mouse; 0/Socs3 protein, mouse; 0/Sodium Channels; 0/Stat3 protein, mouse; 0/Suppressor of Cytokine Signaling Proteins; 133483-10-0/Cytokine Receptor gp130; SY7Q814VUP/Calcium
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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