Mettl3 promotes oxLDL-mediated inflammation through activating STAT1 signaling.

Zhenwei Li,Ning Huangfu,Jianhua Zhu,Xiaomin Chen,Qingqing Xu

doi:10.1002/jcla.24019

Abstract

BackgroundAtherosclerosis (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 AS, but its role in AS is largely unknown. The aim of this study was to investigate the role and mechanism of m6A modification in inflammation triggered by oxidized low‐density lipoprotein (oxLDL) in macrophages during AS.MethodsRAW264.7 macrophage cells were stimulated with 40 μg/ml ox‐LDL, Dot blot, Immunoprecipitation, western blot, Rip and chip experiments were used in our study.ResultsWe found oxLDL stimulation significantly promoted m6A modification level of mRNA in macrophages and knockdown of Methyltransferase‐Like Protein 3 (Mettl3) inhibited oxLDL‐induced m6A modification and inflammatory response. Mettl3 promoted 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 enhanced the interaction between Mettl3 and STAT1 protein, promoting STAT1 transcriptional regulation of inflammatory factor expression in macrophages eventually.ConclusionsThese results indicate that Mettl3 promotes oxLDL‐triggered inflammation through interacting with STAT1 protein and mRNA in RAW264.7 macrophages, suggesting that Mettl3 may be as a potential target for the clinical treatment of AS.

Highlights

Atherosclerosis (AS), the major cause of cardiovascular diseases with its main complications, in particular stroke and myocardial infarction, is a chronic inflammatory disease with lipid accumulation and vascular injury [1]
OxLDL stimulation obviously enhances Methyltransferase-Like Protein 3 (Mettl3) interacting with Signal transducer and activator of transcription 1 (STAT1) protein to promote STAT1 transcriptional regulation of inflammatory factor expression in macrophages, which was 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

Summary

Introduction

Atherosclerosis (AS), the major cause of cardiovascular diseases with its main complications, in particular stroke and myocardial infarction, is a chronic inflammatory disease with lipid accumulation and vascular injury [1]. AS is considered as a chronic inflammatory disease of the arterial wall characterized by lipid accumulation, cell necrosis and local inflammation [6]. Macrophages, the major immune cell population in atherosclerotic lesions, play important roles during AS development, from lesion initiation to plaque rupture [6, 7]. More recent studies reveal that signal transducer and activator of transcription 1 (STAT1) acts crucial roles in the pathology of AS through promoting expressions of several pro-inflammatory and pro-atherogenic mediators in macrophages, and is considered as a novel therapeutical target for AS[11], Targeted inhibition of STATs and IRFs as a potential treatment strategy in cardiovascular disease. Understanding macrophage inflammation during AS appears as a prerequisite to develop novel therapeutic strategies for AS

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