The role of ferroptosis in cell-to-cell propagation of cell death initiated from focal injury in cardiomyocytes

Aims: Ferroptosis has grown in importance as a key factor in ischemia-reperfusion (I/R) injury. This study ex-plores the mechanism underlying fibrotic scarring extending along myofibers in cardiac ischemic injury and demonstrates the integral role of ferroptosis in causing a unique cell death pattern linked to I/R injury.Main methods: Cadaveric hearts from individuals who had ischemic injury were examined by histological assays. We created a novel model of inducing cell death in H9c2 cells, and used it to demonstrate ferroptotic cell death extending in a cell-to-cell manner. Ex vivo Langendorff-perfused hearts were used alongside the model to replicate cell death extension along myofibers while also demonstrating protective effects of a ferroptosis in-hibitor, ferrostatin-1 (Fer-1).Key findings: Human hearts from individuals who had I/R injury demonstrated scarring along myofibers that was consistent with mouse models, suggesting that cell death extended from cell-to-cell. Treatment with Ras-selective lethal 3 (RSL3), a ferroptosis inducer, and exposure to excess iron exacerbated cell death propagation in in vitro models, and inhibition of ferroptosis by Fer-1 blunted this effect in both settings. In ex vivo models, Fer-1 was sufficient to reduce cell death along the myofibers caused by external injury.Significance: The unique I/R injury-induced pattern of cell death along myofibers requires novel injury models that mimic this phenomenon, thus we established new methods to replicate it. Ferroptosis is important in propagating injury between cells and better understanding this mechanism may lead to therapeutic responses that limit I/R injury.

Automated summary

This study demonstrates the crucial role of ferroptosis in causing fibrotic scarring along myofibers in cardiac ischemic injury. By examining cadaveric hearts and using ex vivo experiments, the protective effects of the ferroptosis inhibitor Ferrostatin-1 on ischemia-reperfusion injury were demonstrated.