I-1-deficiency negatively impacts survival in a cardiomyopathy mouse model

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Felix W. Friedrich - , Universitätsklinikum Hamburg-Eppendorf (UKE), Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Autor:in)
  • Hannieh Sotoud - , Universitätsklinikum Hamburg-Eppendorf (UKE), Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Autor:in)
  • Birgit Geertz - , Universitätsklinikum Hamburg-Eppendorf (UKE), Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Autor:in)
  • Silvio Weber - , Technische Universität Dresden, Institut für Pharmakologie und Toxikologie (Autor:in)
  • Frederik Flenner - , Universitätsklinikum Hamburg-Eppendorf (UKE), Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Autor:in)
  • Silke Reischmann - , Universitätsklinikum Hamburg-Eppendorf (UKE), Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Autor:in)
  • Thomas Eschenhagen - , Universitätsklinikum Hamburg-Eppendorf (UKE), Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Autor:in)
  • Lucie Carrier - , Universitätsklinikum Hamburg-Eppendorf (UKE), Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Autor:in)
  • Ali El-Armouche - , Institut für Pharmakologie und Toxikologie, Hochschulmedizin (Medizinische Fakultät und Universitätsklinikum) (Autor:in)

Abstract

Aims: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, diastolic dysfunction and increased interstitial fibrosis. Current treatment is based on beta-adrenoceptor (AR) and calcium channel blockers. Since mice deficient of protein phosphatase-1 inhibitor-1 (I-1), an amplifier in beta-AR signalling, were protected from pathological adrenergic stimulation in vivo, we hypothesized that I-1 ablation could result in an improved outcome in a HCM mouse model. Methods and results: We crossed mice deficient of I-1 with homozygous myosin-binding protein C knock-out (Mybpc3 KO) mice exhibiting cardiac dilatation and reduced survival. Unexpectedly, survival time was shorter in double I-1/. Mybpc3 KO than in single Mybpc3 KO mice. Longitudinal echocardiographic assessment revealed lower fractional area change, and higher diastolic left ventricular inner dimensions and end-diastolic volumes in Mybpc3 KO than in WT mice. In comparison to Mybpc3 KO, double I-1/. Mybpc3 KO presented higher left ventricular end-diastolic volumes, inner dimensions and ventricular surface areas with increasing differences over time. Phosphorylation levels of PKA-downstream targets and mRNA levels of hypertrophic markers did not differ between I-1/. Mybpc3 KO and single Mybpc3 KO mice, except a trend towards higher beta-myosin heavy chain levels in double I-1/. Mybpc3 KO. Conclusion: The data indicate that interference with beta-AR signalling has no long-term benefit in this severe MYBPC3-related cardiomyopathy mouse model.

Details

OriginalspracheEnglisch
Seiten (von - bis)87-94
Seitenumfang8
Fachzeitschrift International journal of cardiology. Heart and Vasculature
Jahrgang8
PublikationsstatusVeröffentlicht - 1 Sept. 2015
Peer-Review-StatusJa

Externe IDs

ORCID /0000-0003-2514-9429/work/151982634

Schlagworte

Schlagwörter

  • Beta-adrenergic signalling, Cardiomyopathy, Hypertrophic cardiomyopathy, Hypertrophy