Downregulated FTO Promotes MicroRNA-155-mediated Inflammatory Response in Cerebral Ischemia/Reperfusion Injury.

This study aimed to elucidate the mechanism for alteration of mA RNA modification in cerebral ischemia/reperfusion(I/R) injury and identify novel therapeutic targets. A rat cerebral I/R injury model was established by middle cerebral artery occlusion (MCAO) followed by reperfusion. Changes in mA RNA modification were evaluated by colorimetric quantification. The expression of the mA methyltransferases METTL3, METTL14, and WTAP, and the demethylases FTO and ALKBH5 were determined using qPCR and western blot analyses. FTO was overexpressed in brain tissues via intracerebroventricular injection of adenoviruses encoding FTO. The protective effect of FTO on mA RNA modification and cerebral I/R injury was assessed. MeRIP assays were used to detect the impact of FTO overexpression on mA modification of pri-miR-155; qPCR analysis was used to identify its maturation. Finally, the role of miR-155 overexpression in the protective effects of FTO on cerebral I/R injury was examined. mA levels of total RNA were increased, and mA methyltransferase FTO expression was decreased in post-I/R injury cerebral tissues. FTO overexpression reversed the increase in mA RNA modification and attenuated cerebral I/R injury. Furthermore, FTO overexpression increased the mA modification of pri-miR-155 and enhanced its maturation to form miR-155. Notably, miR-155 overexpression blunted FTO's protective effect against cerebral I/R injury. We propose that downregulation of FTO expression contributes to increased mA RNA modification in cerebral I/R injury. FTO overexpression reverses increased total mA RNA modification and exerts a protective effect against cerebral I/R injury via downregulating m6A modification of pri-miR-155 to inhibit its maturation process.