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AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure

Previous studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy fo...

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Main Authors: Remes, Anca (Author) , Wagner, Andreas H. (Author) , Schmiedel, Nesrin (Author) , Heckmann, Markus B. (Author) , Ruf, Theresa (Author) , Ding, Lin (Author) , Jungmann, Andreas (Author) , Senger, Frauke (Author) , Katus, Hugo (Author) , Ullrich, Nina D. (Author) , Frey, Norbert (Author) , Hecker, Markus (Author) , Müller, Oliver J. (Author)
Format: Article (Journal)
Language:English
Published: 04 June 2021
In: Basic research in cardiology
Year: 2021, Volume: 116, Pages: 1-12
ISSN:1435-1803
DOI:10.1007/s00395-021-00880-w
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1007/s00395-021-00880-w
Verlag, lizenzpflichtig, Volltext: https://link.springer.com/article/10.1007%2Fs00395-021-00880-w
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Author Notes:Anca Remes, Andreas H. Wagner, Nesrin Schmiedel, Markus Heckmann, Theresa Ruf, Lin Ding, Andreas Jungmann, Frauke Senger, Hugo A. Katus, Nina D. Ullrich, Norbert Frey, Markus Hecker, Oliver J. Müller
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Summary:Previous studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach.
Item Description:Gesehen am 04.11.2021
Physical Description:Online Resource
ISSN:1435-1803
DOI:10.1007/s00395-021-00880-w

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