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

Yiqi Gong; Li Yang; Jun Tang; Jijian Zheng; Nevin Witman; Philipp Jakob; Yao Tan; Minglu Liu; Ying Chen; Huijing Wang; Wei Fu; Wei Wang

doi:10.1007/s12012-021-09709-3

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

Cardiovasc Toxicol. 2022 Feb;22(2):141-151. doi: 10.1007/s12012-021-09709-3. Epub 2021 Nov 24.

Authors

Yiqi Gong^#^{1

2

3}, Li Yang^#^{4

5}, Jun Tang^#⁶, Jijian Zheng⁷, Nevin Witman⁸, Philipp Jakob^{2

3}, Yao Tan¹, Minglu Liu¹, Ying Chen¹, Huijing Wang⁹, Wei Fu^{10

11

12}, Wei Wang¹³

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.
² Department of Cardiology, University Heart Center, University Hospital Zurich, University of Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.
³ Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952, Schlieren, Switzerland.
⁴ Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
⁵ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
⁶ Department of Anesthesiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China.
⁷ Department of Anesthesiology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
⁸ Department of Cell and Molecular Biology, Karolinska Institute, 17177, Stockholm, Sweden.
⁹ Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
¹⁰ Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dong Fang Road, Shanghai, 200127, China. fuweizhulu@163.com.
¹¹ Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. fuweizhulu@163.com.
¹² Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200011, China. fuweizhulu@163.com.
¹³ Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dong Fang Road, Shanghai, 200127, China. wangwei@scmc.com.cn.

^# Contributed equally.

PMID: 34817810
DOI: 10.1007/s12012-021-09709-3

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 (I_f), sodium (Na⁺) channel (I_Na), and calcium (Ca⁺⁺) channel currents (I_Ca) 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 I_Na in low doses (IC₅₀ = 14.2 μM, n = 5) and inhibited I_Ca 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 I_Na and I_Ca 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.

Keywords: Cardiotoxicity; Electrophysiology; Human-induced pluripotent stem cell-derived cardiomyocytes; Yohimbine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / drug effects*
Adrenergic alpha-2 Receptor Antagonists / toxicity*
Arrhythmias, Cardiac / chemically induced*
Arrhythmias, Cardiac / metabolism
Arrhythmias, Cardiac / physiopathology
Calcium Channels / metabolism
Cardiotoxicity
Cell Line
Dose-Response Relationship, Drug
Heart Rate / drug effects
Humans
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism
Induced Pluripotent Stem Cells / drug effects*
Induced Pluripotent Stem Cells / metabolism
Myocytes, Cardiac / drug effects*
Myocytes, Cardiac / metabolism
Sodium Channels / metabolism
Yohimbine / toxicity*

Substances

Adrenergic alpha-2 Receptor Antagonists
Calcium Channels
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Sodium Channels
Yohimbine

Abstract

Publication types

MeSH terms

Substances

Grants and funding