Novel insight of N6-methyladenosine modified subtypes in abdominal aortic aneurysm

Abstract

Background: N6-methyladenosine (m6A) is the most prevalent non-cap reversible modification present in messenger RNAs and long non-coding RNAs, and its dysregulation has been linked to multiple cardiovascular diseases, including cardiac hypertrophy and atherosclerosis. Although limited studies have suggested that m6A modification contributes to abdominal aortic aneurysm (AAA) development, the full landscape of m6A regulators that mediate modification patterns has not been revealed.Methods: To distinguish the m6A methylation subtypes in AAA patients, an unsupervised clustering method was carried out, based on the mRNA levels of 17 m6A methylation regulators. Differentially expressed genes were identified by comparing clusters. An m6Ascore model was calculated using principal component analysis and structured to assess the m6A methylation patterns of single samples. Subsequently, the relationship between the m6Ascore and immune cells and the hallmark gene set was analyzed. Finally, pairs of circRNA-m6A regulators and m6A regulators-m6A related genes were used to establish a network.Results: We identified three m6A methylation subtypes in the AAA samples. The m6Acluster A and C were characterized as more immunologically activated because of the higher abundance of immune cells than that in m6Acluster B. The m6Acluster B was less enriched in inflammatory pathways and more prevalent in pathways related to extracellular matrix stability. Subsequently, we divided the individual samples into two groups according to the m6Ascore, which suggested that a high m6Ascore predicted more active inflammatory pathways and higher inflammatory cell infiltration. A network consisting of 9 m6A regulators and 37 circRNAs was constructed.Conclusion: This work highlighted that m6A methylation modification was highly correlated with immune infiltration of AAA, which may promote the progression of AAA. We constructed an individualized m6Ascore model to provide evidence for individualized treatments in the future.

FKBP11 targeted plasma cells promotes abdominal aortic aneurysm progression through an m6A-dependent mechanism

“…Subsequently, we embarked on the development of a novel m6A-related gene signature AMRMS to forecast the progression of AAA. Previous studies have employed similar bioinformatics approaches to investigate the effects of m6A methylation on the progression or prognosis of AAA [9,[14][15][16][17]. However, these studies only analyzed the expression patterns of m6A modulators, but overlooked the analysis of m6A-modified RNAs, rendering their models for predicting the impact of m6A on AAA incompletely.…”

Epigenetic modifications in abdominal aortic aneurysms: from basic to clinical

“…AAA is characterized by vascular remodeling and progressive dilation ( 1 ), infiltration of lymphocytes and macrophages into the vessel wall, and smooth muscle cell apoptosis ( 108 ). Studies have revealed a significant increase in m6A modification levels in AAA, with elevated m6A posing an increased risk of AAA rupture ( 109 , 110 ). Moreover, differential expression of METTL14, FTO, and YTHDF3 has been observed in various types of inflammatory cells in AAA tissue.…”

N6-methyladenosine-associated genetic variants in NECTIN2 and HPCAL1 are risk factors for abdominal aortic aneurysm

“…The significance of m6A methylation in AAA has been reported, with abnormal m6A modification levels contributing to disturbed RNA metabolism and aberrant gene expression closely linked to AAA incidence and progression. 23 , 24 , 25 However, the correlation between m6A-SNPs and AAA risk in the human population remains unclear. Identifying AAA-associated m6A-SNPs through large-scale GWAS is crucial for understanding the genetic mechanisms underlying m6A modification in AAA pathogenesis and improving the fine mapping of causal variants.…”