Abstract
Ferroptosis is an iron-dependent regulated necrosis. This study aims to evaluate the contribution of ferroptosis to ischemia or reperfusion injury, and lay a basis for precise therapy of myocardial infarction. The Sprague-Dawley (SD) rat hearts were subjected to ischemia for different duration or the hearts were treated with 1 h-ischemia plus different duration of reperfusion. The myocardial injury was assessed by biochemical assays and hematoxylin & eosin (HE) staining. The ferroptosis was evaluated with the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), iron, and malondialdehyde. Iron chelator (deferoxamine) was applied to verify the contribution of ferroptosis to ischemia and reperfusion injury. The results showed that ischemic injury (infarction and CK release) was getting worse with the extension of ischemia, but no significant changes in ferroptosis indexes (ACSL4, GPX4, iron, and malondialdehyde) in cardiac tissues were observed. Differently, the levels of ACSL4, iron, and malondialdehyde were gradually elevated with the extension of reperfusion concomitant with a decrease of GPX4 level. In the ischemia-treated rat hearts, no significant changes in myocardial injury were observed in the presence of deferoxamine, while in the ischemia/reperfusion-treated rat hearts, myocardial injury was markedly attenuated in the presence of deferoxamine concomitant with a reduction of ferroptosis. Based on these observations, we conclude that ferroptosis occurs mainly in the phase of myocardial reperfusion but not ischemia. Thus, intervention of ferroptosis exerts beneficial effects on reperfusion injury but not ischemic injury, laying a basis for precise therapy for patients with myocardial infarction.
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Funding
This work was supported by National Natural Science Foundation of China (No. 81872873 to Jun Peng; No. 81573430 to Xiu-Ju Luo).
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PJ, LXJ, and TLJ conceived and designed the experiments. TLJ, TH, CH, and LNS conducted experiments. TLJ and XXM analyzed the data. TLJ and PJ wrote the manuscript. All authors have read and approved the manuscript.
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The study was done with compliance to the ethics standards and approval from the ethics committee of the Central South University, China.
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Tang, LJ., Luo, XJ., Tu, H. et al. Ferroptosis occurs in phase of reperfusion but not ischemia in rat heart following ischemia or ischemia/reperfusion. Naunyn-Schmiedeberg's Arch Pharmacol 394, 401–410 (2021). https://doi.org/10.1007/s00210-020-01932-z
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DOI: https://doi.org/10.1007/s00210-020-01932-z