Abstract
The membrane components of cardiomyocytes are rich in polyunsaturated fatty acids, which are easily oxidized. Thus, an efficient glutathione-based lipid redox system is essential to maintain cellular functions. However, the relationship between the disruption of the redox system during ischemia-reperfusion (IR), oxidized lipid production, and consequent cell death (ferroptosis) remains unclear. To continuously analyze the metabolite fluctuations that occur during IR injury in the living state, a tubular semipermeable membrane (microdialysis) was implanted in the heart wall. The glutathione is released from the cell during ischemia-reperfusion and is unable to remove intracellular reactive oxygen species. The depletion of intracellular glutathione increases reactive oxygen species and causes ferroptosis due to lipid peroxidation and excessive oxidation of lipids in the cell membrane. Additionally, this extracellular release of glutathione was found to be primarily mediated by multidrug resistance protein 1 (MRP1), a specialized transporter. When MRP1 function was inhibited by drugs, glutathione not only scavenged reactive oxygen species but also reduced oxidized lipids, thereby supporting cardiomyocyte survival. Furthermore, this treatment targeting ferroptosis was found to have some efficacy even when initiated several hours after ischemia-reperfusion injury. Targeting the increase in oxidized lipids observed after 6 hours of myocardial infarction is expected to lead to effective treatment by creating a time advantage before the administration of therapeutic agents.
