Combination of ponatinib with deferoxamine synergistically mitigates ischemic heart injury via simultaneous prevention of necroptosis and ferroptosis
Combination of ponatinib with deferoxamine synergistically mitigates ischemic heart injury via simultaneous prevention of necroptosis and ferroptosis
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普纳替尼与去铁胺联合通过同时预防坏死性凋亡和铁死亡，协同减轻缺血性心脏损伤
DOI：
10.1016/j.ejphar.2021.173999
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发表时间：
2021-03-07
影响因子：
5
通讯作者：
Peng, Jun
中科院分区：
文献类型：
--
作者：
Tu, Hua;Zhou, Yuan-Jing;Peng, Jun
坏死性凋亡、铁死亡和亲环蛋白 D (Cyp D) 依赖性坏死会导致心肌缺血/再灌注 (I/R) 损伤，据报道，ponatinib、去铁胺和环孢菌素分别可抑制坏死性凋亡、铁死亡和 Cyp D 依赖性坏死。本研究旨在探讨普纳替尼、去铁胺和环孢素任意两种组合是否比单药对I/R损伤发挥更好的心脏保护作用。 H9c2细胞经10 h缺氧(H)加4 h复氧(R)建立H/R损伤模型。检查了普纳替尼、去铁胺和环孢素之间的任意两种组合对 H/R 损伤的影响。在此基础上，建立大鼠心脏I/R损伤模型，重点研究普纳替尼、去铁胺及其联合用药对心肌I/R损伤的影响及其机制。在 H/R 处理的 H9c2 细胞中，所有三种药物都可以减轻 H/R 损伤（减少 LDH 释放和坏死百分比）。然而，只有ponatinib与去铁胺的组合才能发挥协同作用，减少H/R损伤，同时抑制坏死性凋亡和铁死亡。预期，在缺血之前或之后给予ponatinib或去铁胺可以抑制I/R处理的大鼠心脏的坏死性凋亡或铁死亡，就像在体外一样，同时减少心肌梗塞面积和肌酸激酶释放，并且联合治疗比单一药物治疗更有效。基于这些观察，我们得出结论，ponatinib 与去铁胺的组合通过同时抑制坏死性凋亡和铁死亡来减少心肌 I/R 损伤。
Necroptosis, ferroptosis and cyclophilin D (Cyp D)-dependent necrosis contribute to myocardial ischemia/ reperfusion (I/R) injury, and ponatinib, deferoxamine and cyclosporine are reported to inhibit necroptosis, ferroptosis and Cyp D-dependent necrosis, respectively. This study aims to explore whether the any two combination between ponatinib, deferoxamine and cyclosporine exerts a better cardioprotective effect on I/R injury than single medicine does. The H9c2 cells were subjected to 10 h of hypoxia (H) plus 4 h of reoxygenation (R) to establish H/R injury model. The effects of any two combination between ponatinib, deferoxamine and cyclosporine on H/R injury were examined. On this basis, a I/R injury model in rat hearts was established to focus on the effect of ponatinib, deferoxamine and their combination on myocardial I/R injury and the underlying mechanisms. In H/R-treated H9c2 cells, all three medicines can attenuate H/R injury (decrease in LDH release and necrosis percent). However, only the combination of ponatinib with deferoxamine exerted synergistic effect on reducing H/R injury, showing simultaneous suppression of necroptosis and ferroptosis. Expectedly, administration of ponatinib or deferoxamine either before or after ischemia could suppress necroptosis or ferroptosis in the I/R-treated rat hearts as they did in vitro, concomitant with a decrease in myocardial infarct size and creatine kinase release, and the combination therapy is more efficient than single medication. Based on these observations, we conclude that the combination of ponatinib with deferoxamine reduces myocardial I/R injury via simultaneous inhibition of necroptosis and ferroptosis.