LAUSR

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 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, but not in the early phase and late phase. In addition, ribavirin treatment (1, 5 and 10 μM) remarkably caused DNA damage which was shown by the increase of γH2AX-positive cells only in the mid-phase and activation of p53 during the differentiation of hiPSCs from mesoderm to cardiomyocytes. Moreover, exposure to ribavirin (5 and 10 μM) markedly upregulated the expression of differentiation blocker lncRNAs Gas5 and HBL1 in the mid-phase and late phase of differentiation. In conclusion, our results suggest that ribavirin is detrimental in cardiac differentiation of hiPSCs, which may be associated with DNA damage and p53 activation. It may provide the evidence for the rational clinical application of ribavirin.