Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China.
Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China.; The Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China.
Toxicology. 2020 Apr 15;435:152422. doi: 10.1016/j.tox.2020.152422. Epub 2020 Feb 26.
Ribavirin has been proven to be an antiviral treatment, whereas there are still risks of hemolysis and congenital malformation. Abnormal cardiac development contributes to the occurrence and development of many heart diseases. However, there is so far no evidence that ribavirin induces human cardiac developmental toxicity. Herein, we employed the cardiac differentiation model of human induced pluripotent stem cells (hiPSCs) to determine the impact of ribavirin on heart development. Our data showed that ribavirin at clinically high concentrations (5 and 10 μM) significantly inhibited the proliferation and differentiation of hiPSCs from mesoderm to cardiac progenitor cells and cardiac progenitor cells to cardiomyocytes, but not from pluripotent status to mesoderm. Meanwhile, DCFH-DA staining revealed that ribavirin could increase ROS content in the mid-phase of differentiation. In addition, ribavirin treatment (1, 5 and 10 μM) remarkably caused DNA damage which was shown by the increase of γH2AX-positive cells and upregulation of the p53 during the differentiation of hiPSCs from mesoderm to cardiac progenitor cells. Moreover, exposuring to ribavirin (5 and 10 μM) markedly upregulated the expression of lncRNAs Gas5 in both mid-phase and late phase of differentiation and HBL1 in the mid-phase. In conclusion, our results suggest that ribavirin is detrimental in cardiac differentiation of hiPSCs, which may be associated with DNA damage, upregulated p53 and increased Gas5. It may provide the evidence for the rational clinical application of ribavirin.
利巴韦林已被证明是一种抗病毒治疗药物，但仍存在溶血和先天畸形的风险。异常的心脏发育是许多心脏病发生和发展的原因。然而，目前尚无证据表明利巴韦林会导致人类心脏发育毒性。在此，我们利用人类诱导多能干细胞（hiPSC）的心脏分化模型来确定利巴韦林对心脏发育的影响。我们的数据表明，利巴韦林在临床高浓度（5 和 10 μM）下显著抑制 hiPSC 从中胚层向心脏祖细胞和心脏祖细胞向心肌细胞的增殖和分化，但不能从多能状态向中胚层分化。同时，DCFH-DA 染色显示利巴韦林可以增加分化中期的 ROS 含量。此外，利巴韦林处理（1、5 和 10 μM）显著导致 DNA 损伤，这表现为 hiPSC 从中胚层向心脏祖细胞分化过程中 γH2AX 阳性细胞的增加和 p53 的上调。此外，暴露于利巴韦林（5 和 10 μM）在分化的中期和晚期明显上调了 lncRNA Gas5 的表达，在中期明显上调了 HBL1 的表达。总之，我们的结果表明利巴韦林对 hiPSC 的心脏分化有害，这可能与 DNA 损伤、p53 上调和 Gas5 增加有关。它可能为利巴韦林的合理临床应用提供证据。
