Liensinine- and Neferine-Induced Cardiotoxicity in Primary Neonatal Rat Cardiomyocytes and Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract

Due to drug-induced potential congestive heart failure and irreversible dilated cardiomyopathies, preclinical evaluation of cardiac dysfunction is important to assess the safety of traditional or novel treatments. The embryos of Nelumbo nucifera Gaertner seeds are a homology of traditional Chinese medicine and food. In this study, we applied the real time cellular analysis (RTCA) Cardio system, which can real-time monitor the contractility of cardiomyocytes (CMs), to evaluate drug safety in rat neonatal CMs and human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). This study showed detailed biomechanical CM contractility in vitro, and provided insights into the cardiac dysfunctions associated with liensinine and neferine treatment. These effects exhibited dose and time-dependent recovery. Neferine showed stronger blocking effect in rat neonatal CMs than liensinine. In addition, the effects of liensinine and neferine were further evaluated on hiPS-CMs. Our study also indicated that both liensinine and neferine can cause disruption of calcium homeostasis. For the first time, we demonstrated the potential cardiac side effects of liensinine or neferine. While the same inhibition was observed on hiPS-CMs, more importantly, this study introduced an efficient and effective approach to evaluate the cardiotoxicity of the existing and novel drug candidates.

Induction of Pluripotent Stem Cell-Derived Cardiomyocyte Toxicity by Supernatant of Long Term-Stored Red Blood Cells in Vitro

“…Unlike primary rat neonatal cardiomyocytes, the beating activity of hiPS-CMs is more stable and is barely influenced by the seeding density of hiPS-CMs or medium changing. Therefore, hiPS-CMs have gained wide acceptance as a biologically relevant in vitro model for drug discovery and cardiotoxicity screens [21, 22]. Compared to cytotoxicity assays on H9C2 cell line, hiPS-CMs are more sensitive for the detection of potential cardiac side effects which can be indicated by the beating patterns of CMs [23].…”

Scaffold Hopping Toward Agomelatine: Novel 3, 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents

“…From above in vitro studies, a reasonable interpretation of the observed in vivo cardiotoxicity could not be reached and more studies are still needed. Interestingly, Neferine, one of the four natural products we used to extract the chemical scaffold in this paper, was reported to possess potential cardiotoxicity by disruption of calcium homeostasis 52 . In our case, compound 6a-1 downregulated the calcium overload in corticorsterone-injured PC12 cells.…”

Aconitine‑induced cardiac arrhythmia in human induced pluripotent stem cell‑derived cardiomyocytes

“…The development of drug evaluation systems remains difficult due to the lack of human cardiomyocyte models and suitable methods. HiPSC-CMs, which have predefined contractile characteristics of native cardiomyocytes, a genetically relevant background and the scope of serving as a model of relevant cardiac disease phenotypes, have provided an opportunity for pre-clinical drug evaluation ( 14 , 24 ). More importantly, hiPSC-CMs also have stable electrophysiological and contractile characteristics, which allows for a wide range of applications, including drug discovery, toxicity testing and cardiac disease research ( 12 , 25 ).…”

“…The RTCA Cardio system allows for the real-time, label-free and non-invasive analysis of cardiomyocyte function. This platform has been used for cardiovascular toxicity screening, drug-induced cardiac contractility evaluation and estimating the risk of drug-induced arrhythmia ( 14 – 17 ).…”