1. Combination of ponatinib with deferoxamine synergistically mitigates ischemic heart injury via simultaneous prevention of necroptosis and ferroptosis.
- Author
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Tu H, Zhou YJ, Tang LJ, Xiong XM, Zhang XJ, Ali Sheikh MS, Zhang JJ, Luo XJ, Yuan C, and Peng J
- Subjects
- Animals, Cell Line, Disease Models, Animal, Drug Synergism, Drug Therapy, Combination, Lipid Peroxidation drug effects, Male, Myocardial Infarction metabolism, Myocardial Infarction pathology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Rats, Sprague-Dawley, Signal Transduction, Rats, Deferoxamine pharmacology, Ferroptosis drug effects, Imidazoles pharmacology, Myocardial Infarction prevention & control, Myocardial Reperfusion Injury prevention & control, Myocytes, Cardiac drug effects, Necroptosis drug effects, Pyridazines pharmacology
- Abstract
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., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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