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  2. 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

  • Eur J Pharmacol. 2021 May 5;898:173999. doi: 10.1016/j.ejphar.2021.173999.
Hua Tu 1 Yuan-Jing Zhou 1 Li-Jing Tang 2 Xiao-Ming Xiong 3 Xiao-Jie Zhang 1 Md Sayed Ali Sheikh 4 Jie-Jie Zhang 5 Xiu-Ju Luo 6 Chuang Yuan 7 Jun Peng 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
  • 2 Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
  • 3 Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
  • 4 Internal Medicine Department, Cardiology, College of Medicine, Jouf University, Skaka, Aljouf, Saudi Arabia.
  • 5 Department of Obstetrics, Xiangya Hospital Central South University, Changsha, China; Hunan Engineering Research Center of Early Life Development and Disease Prevention, Changsha, China.
  • 6 Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
  • 7 Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China. Electronic address: [email protected].
  • 8 Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China. Electronic address: [email protected].
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.

Keywords

Cyclosporine; Cyp D-dependent necrosis; Deferoxamine; Ferroptosis; Myocardial ischemia/reperfusion; Necroptosis; Ponatinib.

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