Mettl3 promotes oxLDL-mediated inflammation through activating STAT1 signaling

Abstract Atherosclerosis (AS) is the main cause of cerebrovascular diseases, and macrophages act important roles during the AS pathological process through regulating inflammation. Modification of the novel N(6)-methyladenine (m6A) RNA is reported to be associated with atherosclerosis, but its role in AS is largely unknown. The aim of this study was to investigate the role and mechanism of m6A modification in oxidised low-density lipoprotein (oxLDL) triggered inflammation in macrophages during AS. Dot blot, Immunoprecipitation, western blot, Rip and Chip experiments were used in our study. We find oxLDL stimulation significantly promotes m6A modification level of mRNA in macrophages and knockdown of Methyltransferase-Like Protein 3 (Mettl3) inhibits oxLDL-induced m6A modification and inflammatory response. Mettl3 promotes oxLDL-induced inflammatory response in macrophages through regulating m6A modification of Signal transducer and activator of transcription 1 (STAT1) mRNA, thereby affecting STAT1 expression and activation. Moreover, oxLDL stimulation obviously enhances Mettl3 interacting with STAT1 protein to promote STAT1 transcriptional regulation of inflammatory factor expression in macrophages, which was also demonstrated in the monocytes from patients with angiographically proven coronary artery disease. These results indicate that Mettl3 promotes inflammatory responses through interacting with STAT1 protein and mRNA in macrophages, suggesting that Mettl3 may be as a potential target for the clinical treatment of atherosclerosis.