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

Author:

Remes Anca,Wagner Andreas H.,Schmiedel Nesrin,Heckmann Markus,Ruf Theresa,Ding Lin,Jungmann Andreas,Senger Frauke,Katus Hugo A.,Ullrich Nina D.,Frey Norbert,Hecker Markus,Müller Oliver J.ORCID

Abstract

AbstractPrevious 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.

Funder

FAZIT Stiftung

Baden-Württemberg Stiftung

Deutsches Zentrum für Herz-Kreislaufforschung

Christian-Albrechts-Universität zu Kiel

Publisher

Springer Science and Business Media LLC

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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