Wang Chi, He Jun, Jin Hong, Xiao Haixin, Peng Shuangqing, Xie Jianwei, Zhang Li, Guo Jiabin
Chinese PLA Center for Disease Control and Prevention, Beijing, 100071, China; School of Public Health, China Medical University, Shenyang, 110122, China.
Chinese PLA Center for Disease Control and Prevention, Beijing, 100071, China.
Chemosphere. 2023 Nov;341:140087. doi: 10.1016/j.chemosphere.2023.140087. Epub 2023 Sep 5.
T-2 toxin, a natural secondary sesquiterpenoid metabolite produced by numerous strains of Fusarium fungi, is prevalent in both contaminated food and the environment. T-2 toxin is known to be highly toxic to the cardiovascular system, but the precise mechanisms that lead to T-2 toxin-induced cardiotoxicity are not yet fully understood. Recent findings indicate that ferroptosis is a pivotal factor in cardiovascular damage and exhibits a strong correlation with the detrimental impacts of T-2 toxin. The present study was designed to examine the involvement of ferroptosis in T-2 toxin-induced cardiac injury. Male mice and human cardiomyocytes were subjected to T-2 toxin for 24 h to induce acute cardiotoxicity for in vivo and in vitro studies, respectively. Our results demonstrated that T-2 toxin increased reactive oxygen species production, malondialdehyde, and decreased glutathione/oxidized glutathione and adenosine triphosphate levels. Furthermore, T-2 toxin was observed to activate ferroptosis, as evidenced by an increase in iron (Fe) concentration and upregulation of prostaglandin endoperoxide synthase 2, downregulation of glutathione peroxidase 4 and ferritin heavy chain 1, as well as ferroptotic morphological alterations. Inhibition of ferroptosis by Liproxstatin-1 reversed T-2 toxin-induced cardiac injury. Additionally, the downregulation of heme oxgenase-1 (HO-1) expression by T-2 toxin exacerbates ferroptosis and oxidative damage, which can be further aggravated by HO-1 inhibition with Sn-protoporphyrin. These findings provide novel insights into the mechanism of T-2 toxin-induced cardiotoxicity and suggest that targeting ferroptosis and HO-1 may represent a promising cardioprotective strategy against T-2 toxin.
T-2毒素是由多种镰刀菌菌株产生的一种天然次生倍半萜类代谢产物，在受污染的食物和环境中都很普遍。已知T-2毒素对心血管系统具有高度毒性，但导致T-2毒素诱导心脏毒性的确切机制尚未完全明确。最近的研究结果表明，铁死亡是心血管损伤的关键因素，并且与T-2毒素的有害影响密切相关。本研究旨在探讨铁死亡在T-2毒素诱导的心脏损伤中的作用。分别对雄性小鼠和人心肌细胞施加T-2毒素24小时，以诱导急性心脏毒性，用于体内和体外研究。我们的结果表明，T-2毒素增加了活性氧的产生、丙二醛含量，并降低了谷胱甘肽/氧化型谷胱甘肽和三磷酸腺苷水平。此外，观察到T-2毒素激活了铁死亡，表现为铁（Fe）浓度增加、前列腺素内过氧化物合酶2上调、谷胱甘肽过氧化物酶4和铁蛋白重链1下调，以及铁死亡形态学改变。Liproxstatin-1抑制铁死亡可逆转T-2毒素诱导的心脏损伤。此外，T-2毒素对血红素加氧酶-1（HO-1）表达的下调加剧了铁死亡和氧化损伤，而用锡原卟啉抑制HO-1可进一步加重这种损伤。这些发现为T-2毒素诱导心脏毒性的机制提供了新的见解，并表明靶向铁死亡和HO-1可能是一种有前景的抗T-2毒素心脏保护策略。
