PCBP2 alleviates myocardial infarction by inhibiting cardiomyocyte ferroptosis via the NDUFS1/NRF2 pathway.

Background: Poly(C) binding protein 2 (PCBP2) was reported to alleviate cardiomyocyte damage, but its molecular mechanism remains unclear. The current study aimed to investigate the role and potential mechanism of PCBP2 in progression of MI.

Methods: An in vivo MI model was established by ligation of the left anterior descending (LAD) branch in mice. PCBP2 expression was detected in Normal and MI groups. H9C2 cells were treated with OGD for 0, 2, 4, and 6 h to screen for optimal time to establish MI model in vitro. H9C2 cells were transfected with pcDNA-PCBP2, and the effect of PCBP2 overexpression on OGD-induced oxidative stress, inflammation and ferroptosis was evaluated. Subsequently, the interaction of PCBP2 with NDUFS1 mRNA was predicted by the Starbase database and verified by RNA-immunoprecipitation (RIP) and RNA-protein pull-down assay. Next, a series of reversal experiments were performed to verify the regulation of PCBP2 on NDUFS1 expression. Then, pcDNA-NDUFS1 was transfected into H9C2 and MIND4-17 (NRF2 protein activator) treated for reversal experiments to assess the effect of NDUFS1 on NRF2-mediated ferroptosis. Finally, LV-PCBP2 and LV-NDUFS1 lentiviral vectors were intrapericardially injected into MI mice, and the role of PCBP2 and NDUFS1 in the progression of MI was verified in vivo.

Results: PCBP2 was downregulated in MI model and OGD-induced H9C2 cells. PCBP2 improved cell proliferation and inhibited oxidative stress, inflammation and ferroptosis in OGD-incubated H9C2 cells. PCBP2 bound with NDUFS1 mRNA and promoted NDUFS1 expression in H9C2 cells, which promoted NRF2 activation by enhancing NRF2 nuclear translocation and inhibited NRF2-mediated ferroptosis. Finally, administration of LV-PCBP2 and LV-NDUFS1 alleviated myocardial tissue injury and MI infarct in mice through suppressing cardiomyocyte ferroptosis and inflammation.

Conclusion: Our results suggested that PCBP2 alleviated MI by inhibiting cardiomyocyte ferroptosis through interacting with NDUFS1 mRNA and activating NRF2-Keap1 pathway.