• Mingcheng Fang, Ting Li, and Zhiyong Wu.
• Department of Cardiology, Fujian Provincial Hospital; Shengli Clinical Medical College of Fujian Medical University, 134 East Street, Fuzhou 350001, China.
• Shock. 2024 Apr 9.

BackgroundMyocardial infarction (MI) is a severe condition that typically results from the ischemia and necrosis of heart muscle. Kruppel-like factor 6 (KLF6) can aggravate myocardial ischemia/reperfusion injury. This work aims to reveal its role and mechanism in hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury.MethodsHuman cardiomyocyte (AC16) was exposed to hypoxic treatment to mimic MI-like cell injury. mRNA expression levels of KLF6 and WT1 associated protein (WTAP) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was detected by western blotting assay. Cell viability was assessed by CCK-8 assay. Cell apoptosis and cell cycle were investigated by flow cytometry. Enzyme-linked immunosorbent assays were conducted to detect IL-1β, TNF-α and IL-6 levels. Fe2+ colorimetric assay kit was used to detect Fe2+ level. MDA Content Assay Kit was used to detect MDA level. Cellular ROS Assay kit was applied to assess ROS level. The association of KLF6 and WTAP was identified by RNA immunoprecipitation assay and dual-luciferase reporter assay.ResultsKLF6 and WTAP expression at mRNA and protein levels were significantly upregulated in serum samples of MI patients and H/R-induced AC16 cells when compared with control groups. KLF6 silencing attenuated H/R-induced AC16 cell apoptosis, inflammatory response, oxidative stress and ferroptosis. Additionally, WTAP stabilized KLF6 mRNA by regulating its m6A modification. Further, WTAP knockdown rescued H/R-induced AC16 cell apoptosis, inflammatory response, oxidative stress and ferroptosis by decreasing KLF6 expression.ConclusionWTAP-mediated m6A modification of KLF6 aggravated hypoxia/reoxygenation-induced apoptosis, inflammatory response, oxidative stress and ferroptosis of human cardiomyocytes, providing a therapeutic strategy for MI.Copyright © 2024 by the Shock Society.

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