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

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

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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.

Original language	English
Article number	1
Journal	npj Regenerative Medicine
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41536-025-00389-z
State	Published - Dec 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

Funding

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.

Funders	Funder number
National Institutes of Health (NIH)	P30GM127607, R15HL168688, R01HL147921, F32HL149140, R01HL166280
National Institutes of Health (NIH)
American the American Heart Association	16SDG29950012
American the American Heart Association
Baylor College of Medicine Mouse Metabolism	R01HL130249, R01DK114356, UM1HG006348, S10OD032380

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Medicine (miscellaneous)
Biomedical Engineering
Developmental Biology
Cell Biology

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10.1038/s41536-025-00389-z

Cite this

Devilée, L. A. C., Salama, A. B. M., Miller, J. M., Reid, J. D., Ou, Q., Baraka, N. M., Abou Farraj, K., Jamal, M., Nong, Y., Rosengart, T. K., Andres, D., Satin, J., Mohamed, T. M. A., Hudson, J. E., & Abouleisa, R. R. E. (2025). Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity. npj Regenerative Medicine, 10(1), Article 1. https://doi.org/10.1038/s41536-025-00389-z

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title = "Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity",

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.",

author = "Devil{\'e}e, \{Lynn A.C.\} and Salama, \{Abou bakr M.\} and Miller, \{Jessica M.\} and Reid, \{Janice D.\} and Qinghui Ou and Baraka, \{Nourhan M.\} and \{Abou Farraj\}, Kamal and Madiha Jamal and Yibing Nong and Rosengart, \{Todd K.\} and Douglas Andres and Jonathan Satin and Mohamed, \{Tamer M.A.\} and Hudson, \{James E.\} and Abouleisa, \{Riham R.E.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41536-025-00389-z",

language = "English",

volume = "10",

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Devilée, LAC, Salama, ABM, Miller, JM, Reid, JD, Ou, Q, Baraka, NM, Abou Farraj, K, Jamal, M, Nong, Y, Rosengart, TK, Andres, D , Satin, J, Mohamed, TMA, Hudson, JE & Abouleisa, RRE 2025, 'Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity', npj Regenerative Medicine, vol. 10, no. 1, 1. https://doi.org/10.1038/s41536-025-00389-z

TY - JOUR

T1 - Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity

AU - Devilée, Lynn A.C.

AU - Salama, Abou bakr M.

AU - Miller, Jessica M.

AU - Reid, Janice D.

AU - Ou, Qinghui

AU - Baraka, Nourhan M.

AU - Abou Farraj, Kamal

AU - Jamal, Madiha

AU - Nong, Yibing

AU - Rosengart, Todd K.

AU - Andres, Douglas

AU - Satin, Jonathan

AU - Mohamed, Tamer M.A.

AU - Hudson, James E.

AU - Abouleisa, Riham R.E.

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

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