Fraxetin attenuates ferroptosis in myocardial infarction via AKT/Nrf2/HO-1 signaling

Background: Myocardial infarction (MI) is the principal cause of mortality globally. Fraxetin (Fra) has antioxidative and anti-inflammatory properties. Nevertheless, the functional action of Fra in the progression of MI has never been elucidated. Method: The in vivo model of MI was set up by ligating left anterior descending artery. The gene expression was tested by qRT-PCR and WB. The 2,3,5-triphenyltetrazolium chloride staining was applied to assess MI size. The cell viability was tested by MTT assay. Commercial kits were utilized to detect the activity of serum LDH and the levels of Fe2+, malondialdehyde (MDA), and glutathione (GSH). Results: Fra treatment could reduce the infraction size and restrain ferroptosis in rats with MI. Moreover, Fra reduced the activity of serum LDH, the accumulation of iron and the MDA level, and increased GSH and glutathione peroxidase 4 (GPX4) in rats with MI. Furthermore, Fra protected H9C2 myocardial cells against OGD/R-induced ferroptosis by up-regulating HO-1. Moreover, Fra activated phosphorylation of AKT and Nrf2 nuclear accumulation in MI in vivo and in vitro models. Notably, silencing Nrf2 enhanced the ferroptosis in H9C2 cells induced by OGD/R, while LY, an inhibitor of AKT phosphorylation, diminished the inhibition of Fra. Conclusion: Fra attenuated MI-induced ferroptosis via AKT/Nrf2/HO-1 signaling, providing a potential therapeutic agent for MI.

Automated summary

Fraxetin treatment reduced infarct size and inhibited ferroptosis in rats with myocardial infarction, while also reducing serum LDH activity and iron accumulation, and activating HO-1 to protect myocardial cells from OGD/R-induced ferroptosis. Fra attenuated MI-induced ferroptosis via AKT/Nrf2/HO-1 signaling pathway.