Work

Fto-Mediated m6A Demethylation of Anxa1 Attenuates Cardiac Ischemia–Reperfusion Injury With Suppression of Nlrp3 Inflammasome Signals

Year: 2025

Type: article

Abstract: Background: Myocardial ischemia-reperfusion (I/R) injury represents the major obstacle to achieving successful therapeutic outcomes in acute myocardial infarction patients. Fat mass and obesity-associated protein (Fto), an N6-methyladenosine (m6A) RNA demethylase, has been shown to protect cardiomyocytes against oxygen-glucose deprivation/reperfusion-mediated injury by regulating annexin A1 (Anxa1) expression in vitro. The present study aims to confirm the cardioprotective role of the Fto/Anxa1 axis using in vivo myocardial I/R injury models. Methods: Wild-type (WT) and Anxa1 knockout (KO) mice underwent 30-min left coronary artery ligation and 2-h reperfusion after intramyocardial delivery of recombinant adeno-associated virus serotype 9 encoding Fto (adFto) or a control vector (adnull). The effects of Fto overexpression on cardiac function, fibrosis, apoptosis, and inflammatory response were examined using echocardiography, Masson’s trichrome staining, western blot analysis, enzyme-linked immunosorbent assay, and immunohistochemical staining. m6A-RNA immunoprecipitation-quantitative polymerase chain reaction quantified Anxa1 mRNA methylation. Results: Fto overexpression by adFto significantly improved cardiac function, reduced serum creatine kinase-myocardial band and troponin T levels, and alleviated cardiac fibrosis in I/R-injured WT mice. Mechanistically, Fto weakened I/R-induced global m6A levels and decreased m6A enrichment on Anxa1 mRNA, thereby enhancing Anxa1 expression. In Anxa1 KO mice, adFto did not confer functional or molecular benefit. Conclusions: Fto enhances Anxa1 and mitigates myocardial I/R injury with suppression of nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain- containing receptor 3 (Nlrp3)-inflammasome signaling in vivo, identifying the Fto-Anxa1 axis as a mechanistic contributor and potential therapeutic target.

Source: Frontiers in Bioscience-Landmark

DOI: 10.31083/fbl42765

Authors: Chaojie He, Haojie Yang, Lijia Xu, Hao Zhang, Huilin Hu

Institution: Jiaxing University

Language: English

Topic: Cardiac Ischemia and Reperfusion

Subfield: Pathology and Forensic Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,500