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

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

doi:10.21203/rs.3.rs-3552794/v1

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

Res Sq [Preprint]. 2023 Nov 30:rs.3.rs-3552794. doi: 10.21203/rs.3.rs-3552794/v1.

Authors

Lynn A C Devilée^{1

2}, Jessica M Miller^{3

4}, Janice D Reid^{1

5}, Abou Bakr M Salama^{3

4

6}, Qinghui Ou³, Madiha Jamal^{3

7}, Yibing Nong⁸, Douglas Andres⁹, Jonathan Satin¹⁰, Tamer M A Mohamed^{3

4}, James E Hudson^{1

5}, Riham R E Abouleisa^{3

4}

Affiliations

¹ QIMR Berghofer Medical Research Institute, Cardiac Bioengineering Laboratory, Brisbane, Queensland, Australia.
² School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
³ Institute of Molecular Cardiology, Department of Medicine, University of Louisville, KY, U.S.A.
⁴ Surgery Department, Baylor College of Medicine, Houston, TX, U.S.A.
⁵ School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
⁶ Faculty of Medicine, Zagazig University, Zagazig, Egypt.
⁷ College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
⁸ Center for Cardiometabolic Science, Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville, Louisville, KY, U.S.A.
⁹ Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, U.S.A.
¹⁰ Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, U.S.A.

Abstract

Cardiomyocytes (CMs) lost during ischemic cardiac injury cannot be replaced due to their limited proliferative capacity, which leads to progressive heart failure. Calcium (Ca²⁺) is an important signal transducer that regulates key cellular processes, but its role in regulating CM proliferation is incompletely understood. 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), but not other Ca²⁺ regulatory proteins (SERCA or RYR), 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 induces the cell cycle in CMs by modulating calcineurin activity and translocating Hoxb13 to the CM nucleus. Together, this represents a robust pathway for regenerative strategies.

Keywords: Calcium; Cardiomyocyte proliferation; Cell cycle; LTCC; RRAD; calcineurin.

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Preprint

Abstract

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