title: Continuous glycoprotein-130-mediated signal transducer and activator of transcription-3 activation promotes inflammation, left ventricular rupture, and adverse outcome in subacute myocardial infarction.
abstract: 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.
  
  
  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.affiliation: Department of Cardiology and Angiology, Medical School Hannover, Hannover, Germany. Hilfiker.denise@mh-hannover.de
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.forename: Praphulla
authors.initials: P
authors.lastname: Shukla
authors.forename: Gunnar
authors.initials: G
authors.lastname: Klein
authors.forename: Arnd
authors.initials: A
authors.lastname: Schaefer
authors.forename: Britta
authors.initials: B
authors.lastname: Stapel
authors.forename: Melanie
authors.initials: M
authors.lastname: Hoch
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
authors.forename: Gregor
authors.initials: G
authors.lastname: Theilmeier
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.forename: Andres
authors.initials: A
authors.lastname: Hilfiker
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
mesh_terms: D000818:Animals; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009205:Myocarditis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D012422:Rupture, Spontaneous / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C508600:IL6 protein, human; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130