Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity

Authors

Lynn A. C. Devilée, The University of Queensland
Abou bakr M. Salama, University of Louisville; Zagazig University
Jessica M. Miller, University of Louisville; Baylor College of Medicine
Janice D. Reid, The University of Queensland
Qinghui Ou, University of Louisville
Nourhan M. Baraka, Baylor College of Medicine; Zagazig University
Kamal Abou Farraj, Baylor College of Medicine
Madiha Jamal, University of Louisville; Alfaisal University
Yibing Nong, University of Louisville
Todd K. Rosengart, Baylor College of Medicine
Douglas A. Andres, University of KentuckyFollow
Jonathan Satin, University of KentuckyFollow
Tamer M. A. Mohamed, University of Louisville; Baylor College of Medicine; Zagazig University
James E. Hudson, The University of QueenslandFollow
Riham R. E. Abouleisa, University of Louisville; Baylor College of MedicineFollow

Abstract

Cardiomyocytes (CMs) lost during ischemic cardiac injury cannot be replaced due to their limited proliferative capacity. Calcium is an important signal transducer that regulates key cellular processes, but its role in regulating CM proliferation is incompletely understood. Here we show a robust pathway for new calcium signaling-based cardiac regenerative strategies. A drug screen targeting proteins involved in CM calcium cycling in human embryonic stem cell-derived cardiac organoids (hCOs) revealed that only the inhibition of L-Type Calcium Channel (LTCC) induced the CM cell cycle. Furthermore, overexpression of Ras-related associated with Diabetes (RRAD), an endogenous inhibitor of LTCC, induced CM cell cycle activity in vitro, in human cardiac slices, and in vivo. Mechanistically, LTCC inhibition by RRAD or nifedipine induced CM cell cycle by modulating calcineurin activity. Moreover, ectopic expression of RRAD/CDK4/CCND in combination induced CM proliferation in vitro and in vivo, improved cardiac function and reduced scar size post-myocardial infarction.

Document Type

Article

Publication Date

1-2025

Notes/Citation Information

© The Author(s) 2025

Digital Object Identifier (DOI)

https://doi.org/10.1038/s41536-025-00389-z

Funding Information

This research was funded by NIH grants F32HL149140 (R.R.E.A.), R01HL147921, P30GM127607, R15HL168688, R01HL166280 (T.M.A.M.), and American Heart Association grant 16SDG29950012 (T.M.A.M). J.E.H. is supported by a Snow Medical Fellowship. Ultrasound experiments were supported by the Baylor College of Medicine Mouse Metabolism and Phenotyping Core which is supported by NIH (S10OD032380, UM1HG006348, R01DK114356, R01HL130249). We would like to acknowledge Beverly Dixon for her technical support in animal care and surgeries.

Repository Citation

Devilée, Lynn A. C.; Salama, Abou bakr M.; Miller, Jessica M.; Reid, Janice D.; Ou, Qinghui; Baraka, Nourhan M.; Farraj, Kamal Abou; Jamal, Madiha; Nong, Yibing; Rosengart, Todd K.; Andres, Douglas A.; Satin, Jonathan; Mohamed, Tamer M. A.; Hudson, James E.; and Abouleisa, Riham R. E., "Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity" (2025). Markey Cancer Center Faculty Publications. 289.
https://uknowledge.uky.edu/markey_facpub/289