METTL14 Promotes Cuproptosis-Associated Changes in Rats With Myocardial Ischemia-Reperfusion Injury

Area of Science:

• Cardiovascular Biology
• Molecular Mechanisms of Disease
• Epigenetics and RNA Modifications

Background:

• Myocardial ischemia-reperfusion injury (MI/RI) remains a significant cause of heart damage.
• Cuproptosis, a copper-dependent cell death pathway, is implicated in various pathologies.
• The role of METTL14 in regulating cuproptosis during MI/RI is not well understood.

Purpose of the Study:

• To investigate the role and mechanism of METTL14-mediated regulation of cuproptosis in MI/RI.
• To determine if METTL14 promotes cuproptosis and exacerbates MI/RI.
• To explore the therapeutic potential of targeting METTL14 in MI/RI.

Main Methods:

• Established a rat model of MI/RI and used H9C2 cells for hypoxia/reoxygenation (H/R) modeling.
• Utilized siRNA targeting METTL14 and ATP7A, RNA immunoprecipitation (RIP) assay, and echocardiography.
• Assessed cell viability, intracellular copper (Cu2+) levels, cardiac function, and protein/mRNA expression of key molecules.

Main Results:

• MI/RI induced cardiac dysfunction, necrosis, increased Cu2+ levels, and altered expression of m6A enzymes, ATP7A, and cuproptosis markers (FDX1, LIAS, DLAT).
• METTL14 knockdown reversed these detrimental changes in vivo and in vitro.
• METTL14 interacted with ATP7A mRNA, and its effects were dependent on ATP7A.

Conclusions:

• METTL14 promotes cuproptosis-associated changes and exacerbates MI/RI.
• Targeting METTL14 may offer a novel therapeutic strategy for MI/RI.
• METTL14's mechanism involves regulating ATP7A and downstream cuproptosis pathways.