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 ro...
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Nature Portfolio
2025-01-01
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| Series: | npj Regenerative Medicine |
| Online Access: | https://doi.org/10.1038/s41536-025-00389-z |
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| author | 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 |
| author_facet | 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 |
| author_sort | Lynn A. C. Devilée |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-160d1a98d65144e7a8f7a14618191dea |
| institution | Kabale University |
| issn | 2057-3995 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Regenerative Medicine |
| spelling | doaj-art-160d1a98d65144e7a8f7a14618191dea2025-01-12T12:11:17ZengNature Portfolionpj Regenerative Medicine2057-39952025-01-0110111910.1038/s41536-025-00389-zPharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activityLynn A. C. Devilée0Abou bakr M. Salama1Jessica M. Miller2Janice D. Reid3Qinghui Ou4Nourhan M. Baraka5Kamal Abou Farraj6Madiha Jamal7Yibing Nong8Todd K. Rosengart9Douglas Andres10Jonathan Satin11Tamer M. A. Mohamed12James E. Hudson13Riham R. E. Abouleisa14QIMR Berghofer Medical Research Institute, Cardiac Bioengineering LaboratoryInstitute of Molecular Cardiology, Department of Medicine, University of LouisvilleInstitute of Molecular Cardiology, Department of Medicine, University of LouisvilleQIMR Berghofer Medical Research Institute, Cardiac Bioengineering LaboratoryInstitute of Molecular Cardiology, Department of Medicine, University of LouisvilleSurgery Department, Baylor College of MedicineSurgery Department, Baylor College of MedicineInstitute of Molecular Cardiology, Department of Medicine, University of LouisvilleCenter for Cardiometabolic Science, Christina Lee Brown Envirome Institute, Department of Medicine, University of LouisvilleSurgery Department, Baylor College of MedicineDepartment of Molecular and Cellular Biochemistry, University of Kentucky College of MedicineDepartment of Physiology, University of Kentucky College of MedicineInstitute of Molecular Cardiology, Department of Medicine, University of LouisvilleQIMR Berghofer Medical Research Institute, Cardiac Bioengineering LaboratoryInstitute of Molecular Cardiology, Department of Medicine, University of LouisvilleAbstract 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.https://doi.org/10.1038/s41536-025-00389-z |
| spellingShingle | 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 Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity npj Regenerative Medicine |
| title | Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity |
| title_full | Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity |
| title_fullStr | Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity |
| title_full_unstemmed | Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity |
| title_short | Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity |
| title_sort | pharmacological or genetic inhibition of ltcc promotes cardiomyocyte proliferation through inhibition of calcineurin activity |
| url | https://doi.org/10.1038/s41536-025-00389-z |
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