Kamga Kapchoup Michelle Vanessa, Hescheler Jürgen, Nguemo Filomain
Centre for Physiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Front Pharmacol. 2023 Jul 12;14:1128382. doi: 10.3389/fphar.2023.1128382. eCollection 2023.
Hydroxychloroquine (HDQ) is an antimalarial drug that has also shown its effectiveness in autoimmune diseases. Despite having side effects such as retinopathy, neuromyopathy and controversial cardiac toxicity, HDQ has been presented and now intensively studied for the treatment and prevention of coronavirus disease 2019 (COVID-19). Recent works revealed both beneficial and toxic effects during HDQ treatment. The cardiotoxic profile of HDQ remains unclear and identifying risk factors is challenging. Here, we used well-established cell-cultured to study the cytotoxic effect of HDQ, mouse induced pluripotent stem cells (miPSC) and their cardiomyocytes (CMs) derivatives were exposed to different concentrations of HDQ. Cell colony morphology was assessed by microscopy whereas cell viability was measured by flow cytometry and impedance-based methods. The effect of HDQ on beating activity of mouse and human induced pluripotent stem cell-derived CMs (miPSC-CMs and hiPSC-CMs, respectively) and mouse embryonic stem cell-derived CMs (mESC-CMs) were captured by the xCELLigence RTCA and microelectrode array (MEA) systems. Our results revealed that 20 µM of HDQ promotes proliferation of stem cells used suggesting that if appropriately monitored, HDQ may have a cardioprotective effect and may also represent a possible candidate for tissue repair. In addition, the field potential signals revealed that higher doses of this medication caused bradycardia that could be reversed with a higher concentration of ß-adrenergic agonist, Isoproterenol (Iso). On the contrary, HDQ caused an increase in the beating rate of hiPSC-CMs, which was further helped upon application of Isoproterenol (Iso) suggesting that HDQ and Iso may also work synergistically. These results indicate that HDQ is potentially toxic at high concentrations and can modulate the beating activity of cardiomyocytes. Moreover, HDQ could have a synergistic inotropic effect with isoproterenol on cardiac cells.
羟氯喹啉（HDQ）是一种抗疟药物，在自身免疫性疾病中也显示出疗效。尽管存在视网膜病变、神经肌肉病变以及存在争议的心脏毒性等副作用，但HDQ已被提出并正在针对2019冠状病毒病（COVID-19）的治疗和预防进行深入研究。近期研究揭示了HDQ治疗期间的有益和毒性作用。HDQ的心脏毒性特征仍不明确，识别风险因素具有挑战性。在此，我们使用成熟的细胞培养方法来研究HDQ的细胞毒性作用，将小鼠诱导多能干细胞（miPSC）及其心肌细胞（CMs）衍生物暴露于不同浓度的HDQ。通过显微镜评估细胞集落形态，而通过流式细胞术和基于阻抗的方法测量细胞活力。HDQ对小鼠和人诱导多能干细胞来源的心肌细胞（分别为miPSC-CMs和hiPSC-CMs）以及小鼠胚胎干细胞来源的心肌细胞（mESC-CMs）跳动活性的影响通过xCELLigence RTCA和微电极阵列（MEA）系统进行记录。我们的结果显示，20µM的HDQ促进了所使用干细胞的增殖，这表明如果进行适当监测，HDQ可能具有心脏保护作用，并且也可能是组织修复的一个潜在候选药物。此外，场电位信号显示，更高剂量的这种药物会导致心动过缓，而更高浓度的β-肾上腺素能激动剂异丙肾上腺素（Iso）可使其逆转。相反，HDQ导致hiPSC-CMs的跳动速率增加，应用异丙肾上腺素（Iso）后进一步增强，这表明HDQ和Iso可能也具有协同作用。这些结果表明，HDQ在高浓度时具有潜在毒性，并且可以调节心肌细胞的跳动活性。此外，HDQ在心脏细胞上可能与异丙肾上腺素具有协同变力作用。
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