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Yohimbine Directly Induces Cardiotoxicity on Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

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Abstract

Yohimbine is a highly selective and potent α2-adrenoceptor antagonist, which is usually treated as an adjunction for impotence, as well for weight loss and natural bodybuilding aids. However, it was recently reported that Yohimbine causes myocardial injury and controversial results were reported in the setting of cardiac diseases. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a model system to explore electrophysiologic characterization after exposure to Yohimbine. HiPSC-CMs were differentiated by employment of inhibitory Wnt compounds. For analysis of electrophysiological properties, conventional whole-cell patch-clamp recording was used. Specifically, spontaneous action potentials, pacemaker currents (If), sodium (Na+) channel (INa), and calcium (Ca++) channel currents (ICa) were assessed in hiPSC-CMs after exposure to Yohimbine. HiPSC-CMs expressed sarcomeric-α-actinin and MLC2V proteins, as well as exhibited ventricular-like spontaneous action potential waveform. Yohimbine inhibited frequency of hiPSC-CMs spontaneous action potentials and significantly prolonged action potential duration in a dose-dependent manner. In addition, rest potential, threshold potential, amplitude, and maximal diastolic potential were decreased, whereas APD50/APD90 was prolonged. Yohimbine inhibited the amplitude of INa in low doses (IC50 = 14.2 μM, n = 5) and inhibited ICa in high doses (IC50 = 139.7 μM, n = 5). Whereas Yohimbine did not affect the activation curves, treatment resulted in left shifts in inactivation curves of both Na+ and Ca++ channels. Here, we show that Yohimbine induces direct cardiotoxic effects on spontaneous action potentials of INa and ICa in hiPSC-CMs. Importantly, these effects were not mediated by α2-adrenoceptor signaling. Our results strongly suggest that Yohimbine directly and negatively affects electrophysiological properties of human cardiomyocytes. These findings are highly relevant for potential application of Yohimbine in patients with atrioventricular conduction disorder.

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Availability of Data and Materials

The data generated from this study are available from the corresponding author upon reasonable request.

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Acknowledgements

All authors appreciate Professor Li Yanxin (Shanghai Children's Medical Center, Shanghai, China) for providing cell resources.

Funding

This study was supported by General Program of National Natural Science Foundation of China (82070430), Shanghai Pujiang Program (18PJD031), Shanghai Collaborative Innovation Center for Translational Medicine (TM201821), Shanghai Natural Science Foundation (20ZR1434500), Science and Technology Development Foundation of Shanghai Pudong (PKJ2020-Y06), the Biomedical Engineering fund of Shanghai Jiao Tong University (YG2021GD04), National Key R&D Program of China (2019YFA0110400), Health Commission of Minhang District, Shanghai (2018MW02).

Author information

Author notes

  1. Yiqi Gong, Jun Tang and Li Yang have contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiothoracic Surgery, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dong Fang Road, Shanghai, 200127, China

    Yiqi Gong, Yao Tan, Minglu Liu, Ying Chen, Wei Fu & Wei Wang

  2. Department of Cardiology, University Heart Center, University Hospital Zurich, University of Zurich, Raemistrasse 100, 8091, Zurich, Switzerland

    Yiqi Gong & Philipp Jakob

  3. Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952, Schlieren, Switzerland

    Yiqi Gong & Philipp Jakob

  4. Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Li Yang

  5. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Li Yang

  6. Department of Anesthesiology, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, 200240, China

    Jun Tang

  7. Department of Anesthesiology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Jijian Zheng

  8. Department of Cell and Molecular Biology, Karolinska Institute, 17177, Stockholm, Sweden

    Nevin Witman

  9. Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Huijing Wang & Wei Fu

  10. Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200011, China

    Wei Fu

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  1. Yiqi Gong
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Contributions

(I) Conception and design: WW, WF, JJZ; (II) administrative support: none; (III) provision of study materials or patients: none; (IV) collection and assembly of data: YQG, LY, YT; (V) data analysis and interpretation: YQG, LY; (VI) manuscript writing: all authors; (VII) final approval of manuscript: all authors.

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Correspondence to Wei Fu or Wei Wang.

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Gong, Y., Yang, L., Tang, J. et al. Yohimbine Directly Induces Cardiotoxicity on Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Cardiovasc Toxicol 22, 141–151 (2022). https://doi.org/10.1007/s12012-021-09709-3

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  • DOI: https://doi.org/10.1007/s12012-021-09709-3

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