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Inducible cardiomyocyte-specific deletion of CaM kinase II protects from pressure overload-induced heart failure

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An Invited Editorial to this article was published on 28 September 2016

Abstract

CaM kinase II (CaMKII) has been suggested to drive pathological cardiac remodeling and heart failure. However, the evidence provided so far is based on inhibitory strategies using chemical compounds and peptides that also exert off-target effects and followed exclusively preventive strategies. Therefore, the aim of this study was to investigate whether specific CaMKII inhibition after the onset of cardiac stress delays or reverses maladaptive cardiac remodeling and dysfunction. Combined genetic deletion of the two redundant CaMKII genes δ and γ was induced after the onset of overt heart failure as the result of pathological pressure overload induced by transverse aortic constriction (TAC). We used two different strategies to engineer an inducible cardiomyocyte-specific CaMKIIδ/CaMKIIγ double knockout mouse model (DKO): one model bases on tamoxifen-inducible mER/Cre/mER expression under control of the cardiac-specific αMHC promoter; the other strategy bases on overexpression of Cre recombinase via cardiac-specific gene transfer through adeno-associated virus (AAV9) under control of the cardiac-specific myosin light chain promoter. Both models led to a substantial deletion of CaMKII in failing hearts. To approximate the clinical situation, CaMKII deletion was induced 3 weeks after TAC surgery. In both models of DKO, the progression of cardiac dysfunction and interstitial fibrosis could be slowed down as compared to control animals. Taken together, we show for the first time that “therapeutic” CaMKII deletion after cardiac damage is sufficient to attenuate maladaptive cardiac remodeling and to reverse signs of heart failure. These data suggest that CaMKII inhibition is a promising therapeutic approach to combat heart failure.

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Acknowledgments

The expert technical assistance of Silvia Harrack, Jutta Krebs, Ulrike Oehl, and Michaela Oestringer is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Molecular Cardiology and Epigenetics, University of Heidelberg, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany

    Michael M. Kreusser, Lorenz H. Lehmann, Nora Wolf, Stanislav Keranov & Johannes Backs

  2. Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Michael M. Kreusser, Lorenz H. Lehmann, Andreas Jungmann, Oliver J. Müller, Hugo A. Katus & Johannes Backs

  3. DZHK (German Centre for Cardiovascular Research), Partner Site, Heidelberg/Mannheim, Germany

    Michael M. Kreusser, Lorenz H. Lehmann, Oliver J. Müller, Hugo A. Katus & Johannes Backs

  4. Department of Molecular Pathology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Hermann-Josef Gröne

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  1. Michael M. Kreusser
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  2. Lorenz H. Lehmann
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  9. Johannes Backs
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Correspondence to Johannes Backs.

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Funding

This work was supported by the Deutsche Forschungsgemeinschaft (BA 2258/2-1, SFB 1118) and by the European Commission (FP7-Health-2010; MEDIA-261409). M.M.K. was supported by the Young Investigator Program of the University of Heidelberg and by a scholarship from the German Cardiac Society (DGK). N.W. was supported by a Cardiology Career Program fellowship of the Department of Cardiology, University of Heidelberg. J.B. and H.A.K. were supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research).

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None declared.

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To this original contribution an invited editorial is available at doi:10.1007/s00395-016-0582-1.

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Kreusser, M.M., Lehmann, L.H., Wolf, N. et al. Inducible cardiomyocyte-specific deletion of CaM kinase II protects from pressure overload-induced heart failure. Basic Res Cardiol 111, 65 (2016). https://doi.org/10.1007/s00395-016-0581-2

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