Naringin attenuates myocardial ischemia-reperfusion injury by promoting mitochondrial translocation of NDUFS1 and suppressing cardiac microvascular endothelial cell ferroptosis.

Abstract

Purpose: Cardiac microvascular injury plays a pivotal role in the progression of myocardial ischemia-reperfusion injury (MI/RI). Previous studies have demonstrated the cardioprotective effects of naringin (Nar) in cardiovascular diseases. However, the involvement of cardiac microvessels in Nar-mediated protection against MI/RI remains unexplored. This study aimed to investigate the impact of Nar on the function of cardiac microvascular endothelial cells (CMECs) in MI/RI rat.

Methods: An MI/RI model was established in rats through ligation of the left anterior descending artery for 45 min followed by 6 h of reperfusion. In vitro, a hypoxia-reoxygenation (H/R) model was established in CMECs by subjecting them to 12 h of hypoxia and 24 h of reoxygenation. A comprehensive set of experimental techniques was employed, including qRT-PCR, western blotting, transmission electron microscopy (TEM), proteomic analysis, ELISA, TTC staining, immunohistochemistry, immunofluorescence, molecular docking, and molecular dynamics simulations.

Results: Our results revealed that Nar significantly enhances cardiac microvascular function by suppressing ferroptosis in CMECs during MI/RI. Mechanistically, phosphorylation of interferon regulatory factor 3 (IRF3) was downregulated in both the hearts of MI/RI rats and CMECs exposed to H/R. Nar effectively upregulated IRF3 phosphorylation, thereby activating the SLC7A11/Gpx4 signaling pathway. Furthermore, Nar facilitated the translocation of NADH ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1) from the cytosol to the mitochondria, enhancing mitochondrial function and mitigating ferroptosis in H/R-treated CMECs.

Conclusion: Nar promoted mitochondrial translocation of NDUFS1, thereby restoring mitochondrial function and inhibited CMECs ferroptosis via activation of the IRF3/SLC7A11/Gpx4 axis.