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Updated: Oct 10, 2025
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
Circular RNA Foxo3 Relieves Myocardial Ischemia/Reperfusion Injury by Suppressing Autophagy via Inhibiting HMGB1 by
Guang Sun1, Jian-Fen Shen2, Xiu-Fang Wei1
1Department of Geriatric Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, People's Republic of China.
Insights
Circular RNA circFoxo3 protects against myocardial infarction (MI) by reducing autophagy and cell damage. It achieves this by targeting KAT7 and HMGB1, offering new therapeutic insights for heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- RNA Biology
Background:
- Myocardial infarction (MI) is a leading global cause of death, driven by coronary artery disease.
- Circular RNAs (circRNAs) are emerging as critical regulators in cardiac pathological processes.
Purpose of the Study:
- To investigate the function of circFoxo3 in myocardial infarction (MI)-induced cardiac injury.
- To elucidate the underlying molecular mechanisms of circFoxo3 in regulating cardiac dysfunction.
Main Methods:
- Utilized a rat model of myocardial infarction (MI) and in vitro cardiomyocyte models subjected to oxygen-glucose deprivation (OGD).
- Assessed the expression levels of circFoxo3, KAT7, and HMGB1.
- Investigated the effects of circFoxo3 overexpression/knockdown on autophagy, apoptosis, inflammation, and cardiomyocyte injury.
- Analyzed the regulatory relationship between circFoxo3, KAT7, and HMGB1 at the promoter level, including histone acetylation and RNA polymerase II enrichment.
Main Results:
- CircFoxo3 was found to be downregulated in the MI rat model.
- Overexpression of circFoxo3 ameliorated cardiac dysfunction and attenuated autophagy in MI rats and OGD-induced cardiomyocytes.
- CircFoxo3 suppressed OGD-induced autophagy, apoptosis, inflammation, and cardiomyocyte injury by inhibiting KAT7 expression, which in turn repressed HMGB1 expression.
- CircFoxo3 reduced KAT7, H3K14ac, and RNA Pol II enrichment on the HMGB1 promoter, while KAT7 or HMGB1 overexpression reversed the protective effects of circFoxo3.
Conclusions:
- Circular RNA circFoxo3 plays a protective role in myocardial ischemia/reperfusion injury.
- CircFoxo3 alleviates cardiac dysfunction and autophagy by targeting the KAT7/HMGB1 signaling pathway.
- This study provides novel mechanistic insights into circFoxo3's role in regulating MI-related cardiac dysfunction.
Introduction:
Myocardial infarction is coronary artery-related heart disease, and the leading cause of mortality globally. Circular RNAs (circRNAs) are a new type of regulatory RNAs and participate in multiple pathological cardiac progression.
Methods:
However, the function of circFoxo3 in MI-induced myocardial injury remains obscure.
Results:
Significantly, we identified that circFoxo3 was downregulated in the MI rat model and the overexpression of circFoxo3 ameliorated MI-induced cardiac dysfunction and attenuated MI-induced autophagy in rat model. Meanwhile, the overexpression of circFoxo3 repressed oxygen-glucose deprivation (OGD)-induced autophagy, apoptosis, inflammation, and injury of cardiomyocyte in vitro. Mechanically, we identified that the expression of KAT7 was reduced by circFoxo3 overexpression in cardiomyocytes. Meanwhile, the expression of HMGB1 was repressed by the depletion of KAT7 in cardiomyocytes. The enrichment of histone H3 lysine 14 acetylation (H3K14ac) and RNA polymerase II (RNA pol II) on HMGB1 promoter was inhibited by the knockdown of KAT7. Moreover, the overexpression of circFoxo3 suppressed HMGB1 expression and KAT7 overexpression rescued the expression of HMGB1 in cardiomyocytes. The enrichment of KAT7, H3K14ac, and RNA poly II on HMGB1 promoter was decreased by circFoxo3 overexpression, while the overexpression of KAT7 could reverse the effect. The overexpression of KAT7 or HMGB1 could reverse circFoxo3-attenuated cardiomyocyte injury and autophagy in vitro. Thus, we conclude that circular RNA circFoxo3 relieved myocardial ischemia/reperfusion injury by suppressing autophagy via inhibiting HMGB1 by repressing KAT7 in MI.
Discussion:
Our finding provides new insight into the mechanism by which circFoxo3 regulates MI-related cardiac dysfunction by targeting KAT7/HMGB1 axis.
