The role of ferroptos in myocardial ischemia/reperfusion injury and the effects of mdivi-1 and ischemic postconditioning

Myocardial ischemia/reperfusion (IR) injury is associated with many cardiovascular diseases and the success of current treatments to reduce the damage and improve the clinical picture remains limited. In order to determine new treatment strategies, it is important to elucidate the pathophysiological mechanism and to draw a road map accordingly and to find new agents to be used in treatment in order to contribute to the success of treatment. Ferroptosis has been identified as an effective form of cell death in myocardial IR injury, and the mechanism of damage is thought to be related to mitochondria. While ischaemic postconditioning (PostC) is a mechanical treatment in myocardial IR injury, mitochondrial fission inhibitör-1 (Mdivi-1) is a pharmacological treatment acting through mitochondria. The aim of this study was to determine the effects of PostC and Mdivi-1 on myocardial IR injury and the role of ferroptosis in both myocardial IR injury and the effect of PostC and Mdivi-1 on myocardial IR injury. In addition, it is aimed to reveal the effects on mitophagy. In the study, 91 male Spraque Dawley rats weighing 300-320 g were divided into two main groups for necrosis area calculations and molecular analysis. IR was performed as 30 minutes ischemia and 120 minutes reperfusion in the left coronary artery. PostC was applied in three periods as 10 seconds ischemia and 10 seconds reperfusion at the beginning of reperfusion. Mdivi-1 was administered intraperitoneally at a dose of 1,2 mg/kg at the beginning of reperfusion. Necrosis area was determined by tetrazolium chloride staining. Acyl-coA synthetase long-chain family member 4 (ACSL4) for ferroptosis, Dynamin-related protein 1 (DRP1) and Parkin levels as mitochondrial parameters were measured by Western blot. For ferroptosis, 12S ribosomal ribonucleic acid type-c mitochondrial open reading frame (MOTS-c) was measured by Enzyme-linked immunosorbent assay, while Micro ribonucleic acid-541-3p (miRNA-541-3p) was measured by Real-time polymerase chain reaction. Necrosis area increased with IR and decreased significantly with PostC and Mdivi-1. DRP1 level significantly increased with IR and decreased with PostC and Mdivi-1. Parkin level increased significantly with IR and decreased with PostC, while the decrease with Mdivi-1 did not reach significance. Among the parameters of ferroptosis, ACSL4 increased significantly with IR but decreased significantly with PostC and Mdivi-1; miRNA-541-3p and MOTS-c decreased with IR but increased significantly with PostC and Mdivi-1. Ferroptosis may be involved in the pathophysiological mechanism of myocardial IR at the level of gene and protein expression, and mitochondrial fission and mitophagy may accompany this mechanism. In myocardial IR injury, Mdivi-1 may be protective by inhibiting mitochondrial fission and ferroptosis without altering mitophagy, and PostC may be protective by inhibiting mitochondrial fission, ferroptosis and mitophagy. MiRNA-541-3p may be involved in the pathophysiology of myocardial IR and in the protection of PostC and Mdivi-1 independently of ferroptosis. MOTS-c may play a role in the protection of PostC and Mdivi-1 through inhibition of ferroptosis.