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Neuregulin-4 protects cardiomyocytes against high-glucose-induced ferroptosis via the AMPK/NRF2 signalling pathway
Pengfei Wang1, Xiaohua Guo1, Hongchao Wang1
1Department of Cardiovascular Medicine, The Second Hospital of Hebei Medical University, Heping West Road No. 215, Shijiazhuang, 050000, China.
Background:
High glucose levels are key factors and key contributors to several cardiovascular diseases associated with cardiomyocyte injury. Ferroptosis, which was identified in recent years, is a mode of cell death caused by the iron-mediated accumulation of lipid peroxides. Neuregulin-4 (Nrg4) is an adipokine that has protective effects against metabolic disorders and insulin resistance. Our previous study revealed that Nrg4 has a protective effect against diabetic myocardial injury, and the aim of this study was to investigate whether Nrg4 could attenuate the occurrence of high glucose-induced ferroptosis in cardiomyocytes.
Methods:
We constructed an in vivo diabetic myocardial injury model in which primary cardiomyocytes were cultured in vitro and treated with Nrg4. Changes in ferroptosis-related protein levels and ferroptosis-related indices in cardiomyocytes were observed. In addition, we performed back-validation and explored signalling pathways that regulate ferroptosis in primary cardiomyocytes.
Results:
Nrg4 attenuated cardiomyocyte ferroptosis both in vivo and in vitro. Additionally, the AMPK/NRF2 signalling pathway was activated during this process, and when the AMPK/NRF2 pathway was inhibited, the beneficial effects of Nrg4 were attenuated.
Conclusion:
Nrg4 antagonizes high glucose-induced ferroptosis in cardiomyocytes via the AMPK/NRF2 signalling pathway.
Insights
Neuregulin-4 (Nrg4) protects heart cells from high glucose-induced ferroptosis, a cell death pathway. This protective effect is mediated by the activation of the AMPK/NRF2 signaling pathway.
Area of Science:
- Cardiovascular Biology
- Cell Death Mechanisms
- Metabolic Disease Research
Background:
- High glucose levels are a significant factor in cardiovascular diseases, causing cardiomyocyte injury.
- Ferroptosis, an iron-dependent cell death, is implicated in these injuries.
- Neuregulin-4 (Nrg4), an adipokine, demonstrates protective effects against metabolic disorders.
Purpose of the Study:
- To investigate if Neuregulin-4 (Nrg4) can mitigate high glucose-induced ferroptosis in cardiomyocytes.
- To elucidate the underlying molecular mechanisms of Nrg4's protective action.
Main Methods:
- Construction of an in vivo diabetic myocardial injury model.
- In vitro culture and treatment of primary cardiomyocytes with Nrg4.
- Analysis of ferroptosis-related protein levels and indices.
- Exploration of the AMPK/NRF2 signaling pathway's role.
Main Results:
- Nrg4 significantly attenuated cardiomyocyte ferroptosis in both in vivo and in vitro models.
- The study identified activation of the AMPK/NRF2 signaling pathway during Nrg4 treatment.
- Inhibition of the AMPK/NRF2 pathway diminished the protective effects of Nrg4.
Conclusions:
- Neuregulin-4 (Nrg4) effectively antagonizes high glucose-induced ferroptosis in cardiomyocytes.
- The protective mechanism involves the activation of the AMPK/NRF2 signaling pathway.
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