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Inhibiting L-type calcium channel promotes cardiomyocyte proliferation through activating the canonical Wnt signaling pathway

Acta Pharmacologica Sinica volume 47, pages 917–931 (2026)Cite this article

Abstract

The adult human heart is incapable of regeneration after myocardial infarction (MI) injury. One potential therapeutic strategy is to enhance the proliferation of resident cardiomyocytes (CMs). In this study, we developed a high-content screening assay based on DNA synthesis in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) to identify small molecules that could promote CM proliferation. In the primary screening, we found that L-type calcium channel (LTCC) blockers induced DNA synthesis of hPSC-CMs. Among the 6 clinically approved calcium channel blockers tested in secondary screening and confirmatory experiments, nimodipine (NM) consistently enhanced CM proliferation both in vitro and in vivo. RNA-Seq analysis revealed that NM activated the canonical Wnt signaling pathway, while inhibiting Wnt signaling blunted the proliferative effect of NM. Lrp5, a co-receptor for Wnt ligands known to interact with LTCC, was found to mediate the effect of NM to promote nuclear localization of β-catenin and CM proliferation. In the MI mouse model established by ligating the left anterior descending coronary artery, administration of NM (10 mg/kg, i.p.) for 7 consecutive days significantly improved cardiac contractile function and enhanced resident CM proliferation, which was attenuated by co-treatment with Wnt inhibitor Wnt-C59 (10 mg/kg, i.p.). Our data suggest that L-type calcium channel blockers that induce CM proliferation may be potentially used in the treatment of MI and heart failure to promote cardiac regeneration.

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Fig. 1: High-content screen on hPSC-CM identifies LTCC inhibitors as potent inducers of CM proliferation.
Fig. 2: NM promotes CM proliferation.
Fig. 3: NM enhances canonical Wnt activity.
Fig. 4: Inhibiting Wnt signaling blunts the pro-proliferative effect of NM.
Fig. 5: NM enhances resident CM proliferation through activating the canonical Wnt signaling pathway in vivo.
Fig. 6: NM improves cardiac contractile function and enhances resident CM proliferation post-MI.

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Data availability

All data associated with this study are present in the paper or the Supplementary Materials. RNA-seq data generated in this study have been deposited into the Gene Expression Omnibus (GEO) database (GSE185542).

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Acknowledgements

This work was funded by Key Research and Development Program, Ministry of Science and Technology of China (2017YFA0105600, 2018YFA0800104), National Natural Science Foundation of China (31771613, 32070823, 92168205, 82400339, 82470404), Natural Science Foundation of Shanghai (24SF1900600, 24ZR1457600), Chinese Society of Cardiology Foundation (CSCF2023B02), Fundamental Research Funds for the Central Universities (22120200411, 22120210073, 22120250374) and Tongji University Medicine-X Interdisciplinary Research Initiative (2025-0553-ZD-10). The graphical abstract was created with BioRender.com. The authors thank the Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai, and the Frontier Science Research Center for Stem Cells, Ministry of Education, for their support. And we thank Yang Dong and Mei-hui Zhang for their technical assistance, Zhen Zhang and Tao P Zhong for their helpful discussions.

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  1. These authors contributed equally: Meng-ying Feng, Yan-song Tang.

Authors and Affiliations

  1. Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiovascular Diseases, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China

    Meng-ying Feng, Yan-song Tang, Su Yao, Hong-jie Zhang, Bi-lin Liu, Shi-qi Huang, Zhao-hui Ou-yang, Min Yuan, Rui Jiang & Ke Wei

  2. Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China

    Rong-rong Huang & Da-chun Xu

  3. Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China

    Guo-hua Gong

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Contributions

KW, MYF, and YST conceived the study. DCX, GHG, and KW supervised the experiments. MYF, SY, and YST performed a high-content screen. MYF, YST, and RRH performed experiments on hPSC-CMs, NRVCs and mice. ZHOY, SQH, RJ, and MY performed NRVC experiments. BLL and YST performed experiments on mice. HJZ performed bioinformatics analysis. KW, MYF, and YST wrote the manuscript with input from all authors.

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Correspondence to Ke Wei.

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Feng, My., Tang, Ys., Yao, S. et al. Inhibiting L-type calcium channel promotes cardiomyocyte proliferation through activating the canonical Wnt signaling pathway. Acta Pharmacol Sin 47, 917–931 (2026). https://doi.org/10.1038/s41401-025-01704-6

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