PUBLICATION
Tankyrase Inhibition Attenuates Cardiac Dilatation and Dysfunction in Ischemic Heart Failure
- Authors
- Wang, H., Segersvärd, H., Siren, J., Perttunen, S., Immonen, K., Kosonen, R., Chen, Y.C., Tolva, J., Laivuori, M., Mäyränpää, M.I., Kovanen, P.T., Sinisalo, J., Laine, M., Tikkanen, I., Lakkisto, P.
- ID
- ZDB-PUB-220911-12
- Date
- 2022
- Source
- International Journal of Molecular Sciences 23(17): (Journal)
- Registered Authors
- Chen, Yu-Chia
- Keywords
- Wnt/β-catenin signaling, ischemic heart failure, miRNA, myocardial infarction, tankyrase
- MeSH Terms
-
- Animals
- Dilatation
- Heart Failure*/drug therapy
- Isoproterenol/pharmacology
- MicroRNAs*/genetics
- Rats
- Tankyrases*/antagonists & inhibitors
- Tankyrases*/metabolism
- Wnt Signaling Pathway
- Zebrafish/metabolism
- beta Catenin/metabolism
- PubMed
- 36077457 Full text @ Int. J. Mol. Sci.
Citation
Wang, H., Segersvärd, H., Siren, J., Perttunen, S., Immonen, K., Kosonen, R., Chen, Y.C., Tolva, J., Laivuori, M., Mäyränpää, M.I., Kovanen, P.T., Sinisalo, J., Laine, M., Tikkanen, I., Lakkisto, P. (2022) Tankyrase Inhibition Attenuates Cardiac Dilatation and Dysfunction in Ischemic Heart Failure. International Journal of Molecular Sciences. 23(17).
Abstract
Hyperactive poly(ADP-ribose) polymerases (PARP) promote ischemic heart failure (IHF) after myocardial infarction (MI). However, the role of tankyrases (TNKSs), members of the PARP family, in pathogenesis of IHF remains unknown. We investigated the expression and activation of TNKSs in myocardium of IHF patients and MI rats. We explored the cardioprotective effect of TNKS inhibition in an isoproterenol-induced zebrafish HF model. In IHF patients, we observed elevated TNKS2 and DICER and concomitant upregulation of miR-34a-5p and miR-21-5p in non-infarcted myocardium. In a rat MI model, we found augmented TNKS2 and DICER in the border and infarct areas at the early stage of post-MI. We also observed consistently increased TNKS1 in the border and infarct areas and destabilized AXIN in the infarct area from 4 weeks onward, which in turn triggered Wnt/β-catenin signaling. In an isoproterenol-induced HF zebrafish model, inhibition of TNKS activity with XAV939, a TNKSs-specific inhibitor, protected against ventricular dilatation and cardiac dysfunction and abrogated overactivation of Wnt/β-catenin signaling and dysregulation of miR-34a-5p induced by isoproterenol. Our study unravels a potential role of TNKSs in the pathogenesis of IHF by regulating Wnt/β-catenin signaling and possibly modulating miRNAs and highlights the pharmacotherapeutic potential of TNKS inhibition for prevention of IHF.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping