Document Detail


Continuous glycoprotein-130-mediated signal transducer and activator of transcription-3 activation promotes inflammation, left ventricular rupture, and adverse outcome in subacute myocardial infarction.
MedLine Citation:
PMID:  20585009     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: In patients with myocardial infarction, high serum levels of interleukin-6 cytokines predict a poor outcome. The common receptor of interleukin-6 cytokines, glycoprotein-130 (gp130), signals via janus kinase/signal transducer and activator of transcription (STAT), cytoplasmic protein tyrosine phosphatase/extracellular signal-regulated kinase, and phosphoinositide-3-kinase/Akt pathways, and the regulation of these pathways depends at least in part on the gp130 tyrosine-757 residue. By analyzing cardiomyocyte-specific gp130(Y757F) mutant mice, we investigated the effect of disturbed gp130 signaling after myocardial infarction. METHODS AND RESULTS: The cardiomyocyte-restricted alpha-myosin heavy chain-Cre-recombinase-loxP system was used to generate mice with gp130(Y757F) mutant cardiomyocytes (alphaMHC-Cre(tg/-);gp130(fl/Y757F) [Y(757)F]); all other cells carried at least 1 functional gp130 gene, ensuring normal gp130 signaling. Y(757)F mice displayed normal cardiac function and morphology at 3 months of age comparable to their nonmutant littermates. In response to myocardial infarction, Y(757)F mice displayed higher mortality associated with increased left ventricular rupture rate, sustained cardiac inflammation, and heart failure. These adverse effects were associated with prolonged and enhanced STAT3 activation and increased expression of interleukin-6 and of the complement-activating mannose-binding lectin C. Pharmacological inhibition of the complement system by cobra venom factor attenuated inflammation, prevented left ventricular rupture, and improved cardiac function in Y(757)F mice. Stronger effects were observed with a genetic reduction of STAT3 (STAT3(flox/+)) restricted to cardiomyocytes in Y(757)F mice, which prevented extensive upregulation of interleukin-6, complement activation, and sustained inflammation and lowered left ventricular rupture rate, heart failure, and mortality in subacute myocardial infarction. CONCLUSIONS: Impaired downregulation of gp130-mediated STAT3 activation in subacute infarction promotes cardiac inflammation, adverse remodeling, and heart failure, suggesting a potential causative role of high interleukin-6 serum levels after myocardial infarction.
Authors:
Denise Hilfiker-Kleiner; Praphulla Shukla; Gunnar Klein; Arnd Schaefer; Britta Stapel; Melanie Hoch; Werner Müller; Michaela Scherr; Gregor Theilmeier; Matthias Ernst; Andres Hilfiker; Helmut Drexler
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-28
Journal Detail:
Title:  Circulation     Volume:  122     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-13     Completed Date:  2010-07-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  145-55     Citation Subset:  AIM; IM    
Affiliation:
Department of Cardiology and Angiology, Medical School Hannover, Hannover, Germany. Hilfiker.denise@mh-hannover.de
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MeSH Terms
Descriptor/Qualifier:
Animals
Cytokine Receptor gp130 / genetics,  metabolism*
Down-Regulation / genetics
Humans
Interleukin-6 / blood,  genetics
Mice
Mice, Mutant Strains
Mutation, Missense
Myocardial Infarction / genetics,  metabolism*,  pathology
Myocarditis / genetics,  metabolism*,  pathology
Myocytes, Cardiac / metabolism,  pathology
Rupture, Spontaneous / genetics,  metabolism
STAT3 Transcription Factor / genetics,  metabolism*
Chemical
Reg. No./Substance:
0/IL6 protein, human; 0/IL6ST protein, human; 0/Il6st protein, mouse; 0/Interleukin-6; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 0/Stat3 protein, mouse; 133483-10-0/Cytokine Receptor gp130
Comments/Corrections
Comment In:
Circulation. 2010 Jul 13;122(2):103-5   [PMID:  20585006 ]

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