METTL3 Promotes Diabetic Atherosclerosis Progression By Mediating MRNA Methylation Of AGE/RAGE Pathway Effector Molecules

PurposeDiabetes is one of the high-risk factors for atherosclerosis and numerous studies have shown that the risk of developing atherosclerosis is much higher in diabetics than in non-diabetics.m6A methylation modification is one of the very important base modifications about RNA.This conserved post-transcriptional regulatory mechanism can regulate many eukaryotic genetic information.m6 A is one of the most prevalent modifications among post-transcriptional modifications and is widely found in t RNA,r RNA,m RNA,mi RNA,lnc RNA and circ RNA.m6 A in eukaryotic cells accounts for m6 A accounts for up to 80% of all RNA base modifications in eukaryotic cells.In order to understand the potential molecular mechanisms of m6 A in diabetic atherosclerosis,we have conducted relevant studies.These explorations and findings have the potential to provide evidence for new prevention and treatment of diabetic cardiovascular complications,and on the other hand,the evidence has the potential to help us find new interventions and treatments.Methods and resultsWe analyzed the m6 A methylation levels of carotid plaques collected from diabetic and non-diabetic patients and found that the m6 A modification levels in carotid plaques were much higher in diabetic patients than in non-diabetic patients.Accordingly,we constructed corresponding high glucose and non-high glucose cell models to validate the results obtained in the clinical samples and found that m6 A modification levels were much higher in endothelial cells treated with high glucose than in non-high glucose treated endothelial cells and identified the m6 A pathway AGE-RAGE and the effectors of this pathway by high throughput sequencing: ICAM-1,VCAM-1 SELE,IL6,EDN-1(which we will collectively refer to as ARSE genes).We demonstrated the regulation of the ARSE genes by METTL3 by knocking down METTL3 in endothelial cells.In addition,we determined the level of regulation of the ARSE gene by METTL3 using real-time fluorescence quantitative PCR.We constructed a diabetes model in APOE mice and found that diabetes exacerbated the development of atherosclerosis and also significantly increased ARSE gene m6 A levels at the plaque.CONCLUSIONSThis study has revealed to some extent that METTL3-mediated m RNA m6 A methylation in diabetes contributes to the development and progression of atherosclerosis by increasing the expression level of ARSE in vascular endothelial cells,leading to increased endothelial inflammation and causing endothelial damage.This provides us with a new direction to prevent and intervene in diabetic atherosclerosis.