GSK3β Exacerbates Myocardial Ischemia/Reperfusion Injury by Inhibiting Myc

Abstract

Myocardial ischemia/reperfusion (MI/R) injury is a life-threatening disease with high morbidity and mortality. Herein, the present study is conducted to explore the regulatory mechanism of GSK3β in MI/R injury regarding cardiomyocyte apoptosis and oxidative stress. The MI/R injury mouse model and hypoxic reoxygenation (H/R) cell model were established. The expression pattern of GSK3β, FTO, KLF5, and Myc was determined followed by their relation validation. Next, loss-of-function experiments were implemented to verify the effect of GSK3β/FTO/KLF5/Myc on cardiomyocyte apoptosis and oxidative stress in the MI/R injury mouse model and H/R cell model. High expression of GSK3β and low expression of FTO, KLF5, and Myc were observed in the MI/R injury mouse model and H/R cell model. GSK3β promoted phosphorylation of FTO and KLF5, thus increasing the ubiquitination degradation of FTO and KLF5. A decrease of FTO and KLF5 was able to downregulate Myc expression, resulting in enhanced cardiomyocyte apoptosis and oxidative stress. These data together supported the crucial role that GSK3β played in facilitating cardiomyocyte apoptosis and oxidative stress so as to accelerate MI/R injury, which highlights a promising therapeutic strategy against MI/R injury.

FTOrepressesNLRP3‐mediated pyroptosis and alleviates myocardial ischemia–reperfusion injury via inhibitingCBL‐mediated ubiquitination and degradation of β‐catenin

“…We further elucidated the upstream regulatory mechanism of CBL. Among m6A eraser proteins (ALKBH5 and FTO), only FTO was found to be down-regulated in myocardial ischemia-reperfusion injury, 14,[31][32][33] which was focused on. M6A is a reversible modification mediated by methylases and demethylases in mRNA, and it takes part in the modulation of mRNA processing, translation, and stability.…”

Human umbilical cord mesenchymal stem cells‐derived exosomal circDLGAP4 promotes angiogenesis after cerebral ischemia–reperfusion injury by regulating miR‐320/KLF5 axis

“…KLF5 function is an important transcription factor in cell proliferation, apoptosis, and tumor formation and is regulated by miRNAs 43 . Low expression of KLF5 has been observed in a mouse model of myocardial I/R injury and H/R cell models 44 . Sun et al reported that miR‐10b‐3p reduced neurological deficits and inflammatory factor expression in the brain of ischemia stroke rats by targeting KLF5 45 .…”

“…43 Low expression of KLF5 has been observed in a mouse model of myocardial I/R injury and H/R cell models. 44 Sun et al reported that miR-10b-3p reduced neurological deficits and inflammatory factor expression in the brain of ischemia stroke rats by targeting KLF5. 45 Our data showed that KLF5 overexpression enhanced the cell viability, migration, and tubule formation in H/R-treated HBMECs, and this process was related to the activation of the PI3K/AKT pathway.…”

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

“…Consequently, knockdown of FTO in infected Vero cells not only increased viral titers, but also increased the gene expression and copy number of the N protein [ 811 ]. The phosphorylation of FTO by GSK-3β and the subsequent degradation of FTO by ubiquitination downregulates the expression of the transcription factor Myc during myocardial ischemia/reperfusion injury, elevating cardiomyocyte apoptosis and oxidative stress levels [ 827 , 828 ]. Thus, the timely deactivation of GSK-3 by melatonin via inhibition of GSK-3 gene expression and the phosphorylation of GSK-3 can increase FTO levels and reduce METTL3 in the early stages of infection to effectively suppress not only viral phase separation by N protein, but also the global modulation of the epitranscriptome by the SARS-CoV-2 virus ( Figure 2 ).…”