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Updated: Mar 19, 2026
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
M6A-modified circArhgap26 attenuates cardiac ischemia‒reperfusion injury by suppressing plakophilin-1 palmitoylation
Ming-Yu Zhang1,2, Dong-Ni Ji3,4, Wen-Yi Qi3,4
1State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Laboratory -Province Key Laboratories of Biomedicine--Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, PR China. zhangmingyu.302@163.com.
Insights
Circular RNAs (circRNAs) like circArhgap26 protect against cardiac ischemia-reperfusion injury by regulating protein stability. Decreased circArhgap26 in patients suggests its potential as a biomarker and therapeutic target for heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- RNA Biology
Background:
- Cardiac ischemia-reperfusion (I/R) injury is a major cause of heart disease with poorly understood mechanisms.
- Circular RNAs (circRNAs) are increasingly recognized for their roles in cardiac function and disease.
Purpose of the Study:
- To investigate the role and mechanism of circArhgap26 in cardiac I/R injury.
- To explore circArhgap26 as a potential diagnostic biomarker and therapeutic target for I/R injury.
Main Methods:
- Identified circArhgap26 and its regulation by m6A modification.
- Utilized a mouse model of cardiac I/R injury with cardiac-specific circArhgap26 overexpression.
- Investigated the molecular mechanism involving PKP1, ZDHHC1, palmitoylation, APAF1, and Caspase signaling.
Main Results:
- circArhgap26 expression was decreased in I/R myocardium and patient plasma.
- Overexpression of circArhgap26 reduced cardiac dysfunction, infarct size, and cardiomyocyte apoptosis in mice.
- circArhgap26 inhibits PKP1 palmitoylation, reducing APAF1 synthesis and Caspase pathway activation, thereby protecting against apoptosis.
Conclusions:
- circArhgap26, regulated by m6A and palmitoylation, mitigates cardiac I/R injury.
- circArhgap26 serves as a potential prognostic biomarker and therapeutic target for I/R injury.
- Findings support circRNA-based therapies for cardiovascular diseases and precision medicine.
Abstract:
Cardiac ischemia‒reperfusion (I/R) injury is a leading cause of disability and mortality worldwide, but the underlying mechanism remains largely unknown. Despite the emerging recognition of circular RNAs (circRNAs) as pivotal regulators of cardiac development and disease, their roles in cardiac I/R injury have yet to be thoroughly investigated. In this study, we identified a circRNA named circArhgap26, which is regulated by m6A modification. The expression of circArhgap26 was significantly decreased in the I/R myocardium. Cardiac-specific overexpression of circArhgap26 ameliorated cardiac dysfunction and reduced the infarct area and cardiomyocyte apoptosis in I/R model mice. Mechanistically, circArhgap26 directly bound to PKP1, thereby inhibiting the interaction between PKP1 and the palmitoyltransferase ZDHHC1. The subsequent palmitoylation of PKP1 and its protein stability are subsequently diminished, leading to a reduction in APAF1 protein synthesis and the inhibition of the Caspase-9/Caspase-3 signaling pathway, thereby mitigating cardiomyocyte apoptosis. Most importantly, the expression of circArhgap26 in the plasma of patients undergoing percutaneous coronary intervention (PCI) was decreased. This study not only elucidates the dual regulatory mechanisms of circArhgap26, m6A modification and posttranslational modification (palmitoylation), in combating I/R injury but also provides a theoretical foundation for circRNA-based therapies. Its dual value as a prognostic biomarker and therapeutic target holds promise for advancing precision cardiovascular medicine and improving outcomes in globally prevalent I/R-related diseases.
