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

Lynn A C Devilée; Abou Bakr M Salama; Jessica M Miller; Janice D Reid; Qinghui Ou; Nourhan M Baraka; Kamal Abou Farraj; Madiha Jamal; Yibing Nong; Todd K Rosengart; Douglas Andres; Jonathan Satin; Tamer M A Mohamed; James E Hudson; Riham R E Abouleisa

doi:10.1038/s41536-025-00389-z

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

NPJ Regen Med. 2025 Jan 11;10(1):1. doi: 10.1038/s41536-025-00389-z.

Authors

Lynn A C Devilée^{1

2}, Abou Bakr M Salama^{3

4

5}, Jessica M Miller^{3

4}, Janice D Reid^{1

6}, Qinghui Ou³, Nourhan M Baraka^{4

7}, Kamal Abou Farraj⁴, Madiha Jamal^{3

8}, Yibing Nong⁹, Todd K Rosengart⁴, Douglas Andres¹⁰, Jonathan Satin¹¹, Tamer M A Mohamed^{3

4

7}, James E Hudson^{12

13}, Riham R E Abouleisa^{14

15}

Affiliations

¹ QIMR Berghofer Medical Research Institute, Cardiac Bioengineering Laboratory, Brisbane, Australia.
² School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia.
³ Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, USA.
⁴ Surgery Department, Baylor College of Medicine, Houston, USA.
⁵ Faculty of Medicine, Zagazig University, Zagazig, Egypt.
⁶ School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.
⁷ Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
⁸ College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
⁹ Center for Cardiometabolic Science, Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville, Louisville, USA.
¹⁰ Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, USA.
¹¹ Department of Physiology, University of Kentucky College of Medicine, Lexington, USA.
¹² QIMR Berghofer Medical Research Institute, Cardiac Bioengineering Laboratory, Brisbane, Australia. [email protected].
¹³ School of Biomedical Sciences, The University of Queensland, Brisbane, Australia. [email protected].
¹⁴ Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, USA. [email protected].
¹⁵ Surgery Department, Baylor College of Medicine, Houston, USA. [email protected].

PMID: 39799185
DOI: 10.1038/s41536-025-00389-z

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.

Abstract

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