Abstract
Background: Myocardial infarction (MI) is one of the leading threats to human health. N6-methyladenosine (m6A) modification, as a pivotal regulator of messenger RNA stability, protein expression, and cellular processes, exhibits important roles in the development of cardiac remodeling and cardiomyocyte contractile function.Methods: The expression levels of m6A regulators were analyzed using the GSE5406 database. We analyzed genome-wide association study data and single-cell sequencing data to confirm the functional importance of m6A regulators in MI. Three molecular subtypes with different clinical characteristics were established to tailor treatment strategies for patients with MI. We applied pathway analysis and differentially expressed gene (DEG) analysis to study the changes in gene expression and identified four common DEGs. Furthermore, we constructed the protein–protein interaction network and confirmed several hub genes in three clusters of MI. To lucubrate the potential functions, we performed a ClueGO analysis of these hub networks.Results: In this study, we identified that the levels of FTO, YTHDF3, ZC3H13, and WTAP were dramatically differently expressed in MI tissues compared with controls. Bioinformatics analysis showed that DEGs in MI were significantly related to modulating calcium signaling and chemokine signaling, and m6A regulators were related to regulating glucose measurement and elevated blood glucose levels. Furthermore, genome-wide association study data analysis showed that WTAP single-nucleotide polymorphism was significantly related to the progression of MI. In addition, single-cell sequencing found that WTAP is widely expressed in the heart tissues. Moreover, we conducted consensus clustering for MI in view of the dysregulated m6A regulators’ expression in MI. According to the expression levels, we found MI patients could be clustered into three subtypes. Pathway analysis showed the DEGs among different clusters in MI were assigned to HIF-1, IL-17, MAPK, PI3K-Akt signaling pathways, etc. The module analysis detected several genes, including BAG2, BAG3, MMP2, etc. We also found that MI-related network was significantly related to positive and negative regulation of angiogenesis and response to heat. The hub networks in MI clusters were significantly related to antigen processing and ubiquitin-mediated proteolysis, RNA splicing, and stability, indicating that these processes may contribute to the development of MI.Conclusion: Collectively, our study could provide more information for understanding the roles of m6A in MI, which may provide a novel insight into identifying biomarkers for MI treatment and diagnosis.
Highlights
Myocardial infarction (MI) is referred to as a heart attack event term in which myocardial cells die because of imbalances between oxygen supply and demand
We observed that FTO, YTHDF3, and ZC3H13 expression levels were largely lower in MI tissues than in non-failing controls (p < 0.01); WTAP expression levels were markedly higher in MI tissues relative to nonfailing controls (p < 0.05)
We observed that the levels of FTO, YTHDF3, ZC3H13, and WTAP were dramatically differently expressed in MI tissues compared with non-failing controls, further demonstrating the crucial roles of m6A regulators in MI, which were consistent with previous reports
Summary
Myocardial infarction (MI) is referred to as a heart attack event term in which myocardial cells die because of imbalances between oxygen supply and demand. Type 1 MI is induced by acute atherosclerotic thrombosis, whereas type 2 MI results from the imbalanced supply and demand of myocardial oxygen without acute atherosclerotic thrombosis (Lu et al, 2015; Sandoval and Jaffe, 2019). The most common cause of MI is blood flow to a part of the heart is reduced or paused, leading to myocardial necrosis. The result of a blood coagulum in the coronary artery is responsible for supplying the heart muscle area. Myocardial infarction (MI) is one of the leading threats to human health. N6-methyladenosine (m6A) modification, as a pivotal regulator of messenger RNA stability, protein expression, and cellular processes, exhibits important roles in the development of cardiac remodeling and cardiomyocyte contractile function
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