AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure.
Animals
Cells, Cultured
Dependovirus
/ genetics
Disease Models, Animal
Endothelin-1
/ toxicity
Genetic Therapy
Genetic Vectors
Heart Failure
/ genetics
Hypertrophy, Left Ventricular
/ genetics
Mice, Inbred C57BL
Myocytes, Cardiac
/ drug effects
NFATC Transcription Factors
/ genetics
Oligonucleotides
/ genetics
Rats, Wistar
Ventricular Function, Left
Ventricular Remodeling
Adeno-associated virus
Cardiac hypertrophy
Decoy oligonucleotide
Heart failure
NFAT
Transcription factor
Journal
Basic research in cardiology
ISSN: 1435-1803
Titre abrégé: Basic Res Cardiol
Pays: Germany
ID NLM: 0360342
Informations de publication
Date de publication:
04 06 2021
04 06 2021
Historique:
received:
04
08
2020
accepted:
18
05
2021
entrez:
5
6
2021
pubmed:
6
6
2021
medline:
15
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34089101
doi: 10.1007/s00395-021-00880-w
pii: 10.1007/s00395-021-00880-w
pmc: PMC8178147
doi:
Substances chimiques
Endothelin-1
0
NFATC Transcription Factors
0
Oligonucleotides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
38Subventions
Organisme : Deutsches Zentrum für Herz-Kreislaufforschung (DE)
ID : 81Z2700204
Organisme : Deutsches Zentrum für Herz-Kreislaufforschung (DE)
ID : 81Z0700201
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