An integrated characterization of contractile, electrophysiological, and structural cardiotoxicity of Sophora tonkinensis Gapnep. in human pluripotent stem cell-derived cardiomyocytes

• Published in: Stem cell research & therapy 2019-01, Vol.10 (1), p.20-15, Article 20
• Main Authors: Wang, Ruiying, Wang, Min, Wang, Shan, Yang, Ke, Zhou, Ping, Xie, Xueheng, Cheng, Qi, Ye, Jingxue, Sun, Guibo, Sun, Xiaobo
• Format: Article
• Language: English
• Subjects: Alkaloids; Alkaloids - adverse effects; Alkaloids - pharmacology; Analysis; Antioxidants; Antioxidants (Nutrients); Asian medicine; Azocines - adverse effects; Azocines - pharmacology; Blood pressure; Calcium (intracellular); Calcium homeostasis; Calcium-binding protein; Cardiac arrhythmia; Cardio-NLCS; Cardiomyocytes; Cardiotoxicity; Cell culture; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell Proliferation - drug effects; Cell Proliferation - physiology; Cell Survival - drug effects; Contractility; Creatine; Creatine kinase; Dehydrogenases; Drug development; Drug discovery; Drug dosages; Electric Impedance; Extracellular Fluid - drug effects; Gene expression; Heart cells; hiPSC-CMs; Homeostasis; Humans; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - physiology; Kinases; L-Lactate dehydrogenase; Lactic acid; Legumes; Malondialdehyde; Meditation; Muscle contraction; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - physiology; Oxidative stress; Pluripotency; Quinolizines - adverse effects; Quinolizines - pharmacology; R&D; Reactive oxygen species; Reactive Oxygen Species - metabolism; Research & development; Sophora; Sophora - chemistry; Sophora tonkinensis; Stem cells; Toxicity; Traditional Chinese medicine; Troponin; Troponin I
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-018-1126-4

Cardiotoxicity remains an important concern in drug discovery and clinical medication. Meanwhile, Sophora tonkinensis Gapnep. (S. tonkinensis) held great value in the clinical application of traditional Chinese medicine, but cardiotoxic effects were reported, with matrine, oxymatrine, cytisine, and sophocarpine being the primary toxic components. In this study, impedance and extracellular field potential (EFP) of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were recorded using the cardio non-labeled cell function analysis and culture system (Cardio-NLCS). The effects of matrine, oxymatrine, cytisine, and sophocarpine (2, 10, 50 μM) on cell viability; level of lactate dehydrogenase (LDH), creatine kinase MB isoenzyme (CK-MB), and cardiac troponin I (CTn-I); antioxidant activities; production of reactive oxygen species (ROS) and malondialdehyde (MDA); and disruption of intracellular calcium homeostasis were also added into the integrated assessment. The results showed that matrine and sophocarpine dose-dependently affected both impedance and EFP, while oxymatrine and cytisine altered impedance significantly. Our study also indicated that cardiotoxicity of matrine, oxymatrine, cytisine, and sophocarpine was related to the disruption of calcium homeostasis and oxidative stress. Four alkaloids of S. tonkinensis showed significant cardiotoxicity with dose dependence and structural cardiotoxicity synchronized with functional changes of cardiomyocytes. This finding may provide guidance for clinical meditation management. Furthermore, this study introduced an efficient and reliable approach, which offers alternative options for evaluating the cardiotoxicity of the listed drugs and novel drug candidates.