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PCBP2 alleviates myocardial infarction by inhibiting cardiomyocyte ferroptosis via the NDUFS1/NRF2 pathway
Qianrong Zhang1, Aiping Jin1, Haijuan Cheng1
1Department of Geriatric Cardiovascular Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China.
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.
Insights
Poly(C) binding protein 2 (PCBP2) alleviates myocardial infarction (MI) by inhibiting ferroptosis. PCBP2 interacts with NDUFS1 mRNA, activating the NRF2 pathway to protect heart cells from damage.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cellular Pathology
Background:
- Poly(C) binding protein 2 (PCBP2) is known to mitigate cardiomyocyte damage, but its precise molecular mechanisms in myocardial infarction (MI) are not fully understood.
- Investigating PCBP2's role is crucial for understanding and potentially treating MI progression.
Purpose of the Study:
- To elucidate the role and molecular mechanism of PCBP2 in the progression of myocardial infarction (MI).
- To determine if PCBP2 influences oxidative stress, inflammation, and ferroptosis in cardiomyocytes.
Main Methods:
- Establishment of in vivo (mouse LAD ligation) and in vitro (OGD-treated H9C2 cells) MI models.
- Overexpression of PCBP2 and assessment of its effects on OGD-induced cellular damage.
- Prediction and validation of PCBP2 interaction with NDUFS1 mRNA using bioinformatics and biochemical assays (RIP, pull-down).
- In vivo validation using lentiviral vectors for PCBP2 and NDUFS1 in a mouse MI model.
Main Results:
- PCBP2 expression was found to be downregulated in both in vivo and in vitro MI models.
- PCBP2 overexpression protected H9C2 cells from OGD-induced oxidative stress, inflammation, and ferroptosis.
- PCBP2 directly binds to NDUFS1 mRNA, promoting its expression and subsequently activating NRF2 signaling, which inhibits ferroptosis.
- In vivo administration of PCBP2 and NDUFS1 ameliorated myocardial injury and infarct size by suppressing ferroptosis and inflammation.
Conclusions:
- PCBP2 plays a protective role in myocardial infarction by inhibiting cardiomyocyte ferroptosis.
- The mechanism involves PCBP2 interacting with NDUFS1 mRNA to activate the NRF2-Keap1 pathway.
- Targeting PCBP2 and NDUFS1 presents a potential therapeutic strategy for mitigating MI progression.
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