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Published on: January 10, 2025
3'-Methoxypuerarin Ameliorates Myocardial Ischemia/Reperfusion-Induced Pyroptosis via Regulating IGF2BP1/m6A/NLRP3
Haiyan Zhou1, Huan Zhou1, Chao Li1
1Department of Cardiovascular Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
Aims:
This study aimed to investigate the protective effects of 3'-Methoxypuerarin (3'-MOP) on myocardial ischemia-reperfusion injury (MIRI) and elucidate its underlying mechanisms. Specifically, we examined its role in modulating N6-methyladenosine (m6A) methylation and suppressing cardiomyocyte pyroptosis in both in vivo and in vitro models.
Results:
In vivo, treatment with 3'-MOP markedly reduced myocardial infarct size, preserved cardiac function, and alleviated histopathological injury following ischemia/reperfusion. Consistently, 3'-MOP suppressed m6A methylation and significantly decreased the expression of pyroptosis-related proteins, including NLRP3, cleaved GSDMD, cleaved Caspase-1, IL-1β, and IL-18. In vitro, 3'-MOP decreased m6A methylation, destabilized NLRP3 mRNA, and inhibited pyroptosis in hypoxia/reoxygenation-induced cardiomyocytes. Mechanistically, 3'-MOP disrupted the interaction between insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) and NLRP3 mRNA, regulated m6A modification at predicted NLRP3 sites, and promoted mRNA degradation, thereby mimicking the effects of si-IGF2BP1 and attenuating pyroptottenuating pyroptosis.Conclusion and Innovation:3'-MOP exerts cardioprotective effects against MIRI by modulating m6A methylation and inhibiting pyroptosis. This study is the first to demonstrate that 3'-MOP regulates cardiomyocyte pyroptosis via the m6A/IGF2BP1-NLRP3 axis, providing a novel epitranscriptomic mechanism for cardioprotection against MIRI. Antioxid. Redox Signal. 44, 103-117.
Insights
3'-Methoxypuerarin (3'-MOP) protects the heart from injury by reducing cell death and inflammation. This study reveals its novel mechanism involving N6-methyladenosine (m6A) methylation and the IGF2BP1-NLRP3 pathway.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Epitranscriptomics
Background:
- Myocardial ischemia-reperfusion injury (MIRI) is a major cause of heart damage.
- Cardiomyocyte pyroptosis, a form of inflammatory cell death, exacerbates MIRI.
- N6-methyladenosine (m6A) methylation plays a role in regulating cellular processes, including inflammation and cell death.
Purpose of the Study:
- To investigate the protective effects of 3 -Methoxypuerarin (3 -MOP) against MIRI.
- To elucidate the underlying mechanisms, focusing on m6A methylation and cardiomyocyte pyroptosis.
- To explore the role of the IGF2BP1-NLRP3 axis in 3 -MOP-mediated cardioprotection.
Main Methods:
- In vivo studies using rodent models of MIRI to assess infarct size, cardiac function, and histology.
- In vitro studies using cultured cardiomyocytes subjected to hypoxia/reoxygenation.
- Analysis of m6A methylation levels, pyroptosis markers (NLRP3, Caspase-1, GSDMD, IL-1β, IL-18), and the interaction between IGF2BP1 and NLRP3 mRNA.
Main Results:
- 3 -MOP treatment significantly reduced myocardial infarct size and improved cardiac function in vivo.
- 3 -MOP suppressed m6A methylation and inhibited pyroptosis in both in vivo and in vitro models.
- Mechanistically, 3 -MOP disrupted the IGF2BP1-NLRP3 mRNA interaction, leading to NLRP3 mRNA degradation and reduced pyroptosis.
Conclusions:
- 3 -MOP exerts significant cardioprotective effects against MIRI.
- The cardioprotection is mediated by the modulation of m6A methylation and the inhibition of cardiomyocyte pyroptosis.
- This study identifies a novel epitranscriptomic mechanism involving the m6A/IGF2BP1-NLRP3 axis for 3 -MOP-induced cardioprotection in MIRI.
