Melatonin alleviates doxorubicin-induced mitochondrial oxidative damage and ferroptosis in cardiomyocytes by regulating YAP expression

In this study, we established a Dox-induced cardiotoxicity model in H9c2 cardiomyocytes, zebrafish, and SD rats to explore the mechanism by which Mel alleviates Dox-induced cardiotoxicity. In vivo and in vitro experiments showed that Dox significantly decreased the viability of H9c2 cells, induced apoptosis, myocardial injury, and effectively up-regulated the expression of p-YAP but down-regulated the expression of YAP. Furthermore, we found that Dox significantly up-regulated the expression of ferroptosis-associated protein ACSL4 and down-regulated expression of GPX4. Interestingly, these effects of Dox were reversed following treatment with Mel, indicating that ferroptosis mediated the protective effects of Mel against Dox-induced cardiomyocyte injury. Furthermore, we used YAP-siRNA in vitro and verteporfin (Ver) in vivo to downregulate the expression level of YAP. The results showed that YAP downregulation abolished the protective effects of Mel including apoptosis, mitochondrial lipid peroxidation, and ferroptosis. Collectively, these results show that Mel regulates ferroptosis by modulating YAP expression to counteract Dox-induced cardiotoxicity.PMID:35093381 | DOI:10.1016/j.taap.2022.115902
Source: Toxicology and Applied Pharmacology - Category: Toxicology Authors: Source Type: research