Network Modeling Predicts How DYRK1A Inhibition Promotes Cardiomyocyte Cycling after Ischemic/Reperfusion Injury
Bryce C Murillo1, Alexander Young2, Kaitlyn L Wintruba3
1Department of Pharmacology University of Virginia, Charlottesville VA, USA.
Abstract:
The adult mammalian heart has a limited ability to regenerate lost myocardium following myocardial infarction (MI), largely due to the poor proliferative capacity of cardiomyocytes. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a known regulator of cell quiescence, though the mechanisms underlying its function remain unclear. Previous studies have shown that pharmacological inhibition of DYRK1A using harmine induces cardiomyocyte cell cycle re-entry after ischemia/reperfusion (I/R) MI. Here, we developed a computational network model of DYRK1A-mediated regulation of the cell cycle, which predicts how DYRK1A inhibition promotes cardiomyocyte re-entry. To validate these predictions, we tested selective DYRK1A inhibitors and observed robust induction of cell cycle activity in neonatal rat cardiomyocytes (NRCMs). Integrating our network model with bulk RNA-sequencing data from DYRK1A inhibitor-treated NRCMs, we identified E2F1 as a key transcriptional driver of cell cycle gene expression. Finally, we demonstrate that both pharmacological and post-developmental inhibition of DYRK1A enhances heart function and increases cardiomyocyte cycling following I/R MI. Our findings suggest that functional recovery induced by small molecule inhibitor of DYRK1A is mediated by the induction of cycling cardiomyocytes.
Insights
Inhibiting DYRK1A promotes heart regeneration after myocardial infarction by enabling cardiomyocyte cell cycle re-entry. This approach improves heart function and offers a new therapeutic strategy for cardiac repair.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Regenerative Medicine
Background:
- Adult mammalian heart regeneration is limited by cardiomyocyte proliferation.
- Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) regulates cell quiescence, but its precise role in cardiomyocytes is unclear.
- Pharmacological DYRK1A inhibition has shown potential in promoting cardiomyocyte cell cycle re-entry after myocardial infarction (MI).
Purpose of the Study:
- To elucidate the mechanisms by which DYRK1A inhibition promotes cardiomyocyte cell cycle re-entry.
- To validate the therapeutic potential of DYRK1A inhibition in a preclinical model of cardiac injury.
Main Methods:
- Development of a computational network model of DYRK1A-mediated cell cycle regulation.
- Testing selective DYRK1A inhibitors in neonatal rat cardiomyocytes (NRCMs).
- Integration of network model with bulk RNA-sequencing data and in vivo studies using a mouse model of ischemia/reperfusion (I/R) MI.
Main Results:
- The computational model predicted DYRK1A inhibition's role in cardiomyocyte cell cycle re-entry.
- DYRK1A inhibitors robustly induced cell cycle activity in NRCMs.
- E2F1 was identified as a key transcriptional driver of cell cycle gene expression.
- Pharmacological and post-developmental DYRK1A inhibition improved heart function and increased cardiomyocyte cycling post-I/R MI.
Conclusions:
- DYRK1A inhibition is a viable strategy to enhance cardiomyocyte proliferation and cardiac repair.
- The findings highlight E2F1 as a critical mediator in DYRK1A-regulated cell cycle progression.
- Small molecule inhibition of DYRK1A offers a promising therapeutic avenue for treating myocardial infarction.
