Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.
Institute of Translational Medicine, Zhejiang University, Hangzhou, China.
J Cell Mol Med. 2018 Sep;22(9):4221-4235. doi: 10.1111/jcmm.13702. Epub 2018 Jul 11.
Cadmium, a highly ubiquitous toxic heavy metal, has been widely recognized as an environmental and industrial pollutant, which confers serious threats to human health. The molecular mechanisms of the cadmium-induced cardiotoxicity (CIC) have not been studied in human cardiomyocytes at the cellular level. Here we showed that human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) can recapitulate the CIC at the cellular level. The cadmium-treated hPSC-CMs exhibited cellular phenotype including reduced cell viability, increased apoptosis, cardiac sarcomeric disorganization, elevated reactive oxygen species, altered action potential profile and cardiac arrhythmias. RNA-sequencing analysis revealed a differential transcriptome profile and activated MAPK signalling pathway in cadmium-treated hPSC-CMs, and suppression of P38 MAPK but not ERK MAPK or JNK MAPK rescued CIC phenotype. We further identified that suppression of PI3K/Akt signalling pathway is sufficient to reverse the CIC phenotype, which may play an important role in CIC. Taken together, our data indicate that hPSC-CMs can serve as a suitable model for the exploration of molecular mechanisms underlying CIC and for the discovery of CIC cardioprotective drugs.
镉是一种广泛存在的有毒重金属，已被广泛认为是环境和工业污染物，对人类健康构成严重威胁。在细胞水平上，尚未研究镉诱导的心肌毒性（CIC）在人原代心肌细胞中的分子机制。在这里，我们表明，人多能干细胞衍生的心肌细胞（hPSC-CMs）可以在细胞水平上再现 CIC。用镉处理的 hPSC-CMs 表现出细胞表型，包括细胞活力降低、细胞凋亡增加、心肌肌节排列紊乱、活性氧水平升高、动作电位谱改变和心律失常。RNA 测序分析显示，镉处理的 hPSC-CMs 中存在差异转录组谱和激活的 MAPK 信号通路，抑制 P38 MAPK 而不是 ERK MAPK 或 JNK MAPK 可挽救 CIC 表型。我们进一步发现，抑制 PI3K/Akt 信号通路足以逆转 CIC 表型，这可能在 CIC 中起重要作用。总之，我们的数据表明，hPSC-CMs 可以作为探索 CIC 分子机制和发现 CIC 心脏保护药物的合适模型。
