AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure.
Anca RemesAndreas H WagnerNesrin SchmiedelMarkus HeckmannTheresa RufLin DingAndreas JungmannFrauke SengerHugo A KatusNina D UllrichNorbert FreyMarkus HeckerOliver J MüllerPublished in: Basic research in cardiology (2021)
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.
Keyphrases
- heart failure
- poor prognosis
- left ventricular
- nuclear factor
- transcription factor
- binding protein
- blood pressure
- high glucose
- oxidative stress
- stem cells
- angiotensin ii
- immune response
- spinal cord injury
- endothelial cells
- coronary artery
- young adults
- zika virus
- skeletal muscle
- mesenchymal stem cells
- aortic valve
- quantum dots
- pulmonary hypertension
- drug delivery
- inflammatory response
- drug induced
- pulmonary artery
- cancer therapy
- stress induced