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Updated: Jul 28, 2026
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
Lnc-ANRIL Protects Against Myocardial Ischemia-Reperfusion Injury by Suppressing Ferroptosis via the miR-7238-3p/GPX4
Yijun Liu1, Binhua Wu2,3, Yunhao Shao2
1Department of Anesthesiology, The First Affiliated Hospital, Jinan University, Guangzhou 510630, Guangdong, China.
Insights
Myocardial ischemia-reperfusion injury (MI/RI) triggers ferroptosis by downregulating lncRNA ANRIL, which normally suppresses miR-7238-3p and maintains GPX4 levels. Upregulating lnc-ANRIL protects against MI/RI-induced ferroptosis.
Area of Science:
- Cardiovascular Biology
- Cell Death Mechanisms
- Molecular Cardiology
Background:
- Myocardial infarction (MI) is a major cause of death, and reperfusion therapy can paradoxically cause myocardial ischemia-reperfusion injury (MI/RI).
- Ferroptosis, an iron-dependent cell death pathway involving lipid peroxidation, contributes significantly to MI/RI.
- The role of long non-coding RNA ANRIL in MI/RI-induced ferroptosis remains largely unknown.
Purpose of the Study:
- To investigate the role of lncRNA ANRIL in myocardial ischemia-reperfusion injury (MI/RI).
- To elucidate the molecular mechanism by which lncRNA ANRIL influences ferroptosis during MI/RI.
- To explore lncRNA ANRIL as a potential therapeutic target for MI/RI.
Main Methods:
- Established a mouse model of myocardial infarction and reperfusion (MI/R) and used in vitro hypoxia-reoxygenation models with cardiomyocytes.
- Manipulated lnc-ANRIL expression (overexpression and silencing) and assessed ferroptosis markers (ROS, MDA, Fe2+, GPX4, ACSL4).
- Utilized bioinformatics prediction and dual-luciferase assays to validate the interaction between lnc-ANRIL, miR-7238-3p, and GPX4.
Main Results:
- Myocardial ischemia-reperfusion injury (MI/RI) activated ferroptosis, characterized by decreased GPX4 and increased ACSL4, ROS, malondialdehyde, and Fe2+.
- Lnc-ANRIL expression was reduced in MI/R conditions; its overexpression attenuated ferroptosis, while silencing exacerbated it.
- Lnc-ANRIL functions as a molecular sponge for miR-7238-3p, inhibiting miR-7238-3p's suppression of GPX4 expression.
Conclusions:
- Myocardial ischemia-reperfusion injury (MI/RI) leads to ferroptosis by downregulating lnc-ANRIL, which releases inhibition on miR-7238-3p, subsequently suppressing GPX4.
- Lnc-ANRIL exerts a protective effect against MI/RI-induced ferroptosis through the miR-7238-3p/GPX4 signaling pathway.
- Targeting the lnc-ANRIL/miR-7238-3p/GPX4 axis presents a promising therapeutic strategy for myocardial ischemia-reperfusion injury.
Background/Aims:
Myocardial infarction remains a leading cause of cardiovascular morbidity and mortality. Although reperfusion therapy restores myocardial blood flow, it can induce myocardial ischemia-reperfusion injury (MI/RI). Ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid reactive oxygen species, contributes to MI/RI and is characterized by downregulation of GPX4 and upregulation of ACSL4. LncRNA ANRIL is aberrantly expressed in acute myocardial infarction and may provide myocardial protection, but its role in MI/RI-induced ferroptosis is unclear.
Methods:
A mouse MI/R model was established by ligating the left anterior descending coronary artery in C57BL/6 mice. HL-1 and H9C2 cardiomyocytes underwent hypoxia-reoxygenation to simulate MI/RI in vitro. Lnc-ANRIL was overexpressed using pEGFP-lnc-ANRIL or silenced using siANRIL. Ferroptosis indicators (ROS, malondialdehyde, Fe2+, GPX4, ACSL4) were assessed. Candidate miRNAs targeting lnc-ANRIL and GPX4 were predicted (miRDB) and validated by dual-luciferase assays.
Results:
Ferroptosis was activated in MI/R tissues and hypoxia-reoxygenation-treated cardiomyocytes, with decreased GPX4, increased ACSL4, and elevated ROS, malondialdehyde, and Fe2+. Lnc-ANRIL expression was reduced. Overexpression of lnc-ANRIL attenuated ferroptosis markers and increased GPX4, whereas lnc-ANRIL silencing exacerbated ferroptosis. Mechanistically, lnc-ANRIL acted as a sponge for miR-7238-3p, which targets the 3'-UTR of GPX4 to suppress expression. Overexpression of miR-7238-3p enhanced ferroptosis and cardiomyocyte damage.
Conclusion:
MI/RI downregulates lnc-ANRIL, relieving inhibition of miR-7238-3p and suppressing GPX4, thereby triggering ferroptosis in cardiomyocytes. Lnc-ANRIL protects against MI/RI-induced ferroptosis via the miR-7238-3p/GPX4 axis, suggesting a potential therapeutic target.
