MiRNA-miRNA interaction network in peripheral blood of patients with myocardial infarction: a gene expression meta-analysis

In recent years, investigations have revealed that microRNAs (miRNAs) can bind together and form a miRNA-miRNA-mRNA regulatory network that alters the consequence of miRNA-mRNA interaction. If we consider the miRNA that binds to mRNA as the primary miRNA and the miRNA that binds to the primary miRNA as the secondary one, secondry miRNAs can act as master regulators upstream of primary miRNAs and their target mRNAs. One of the distinguishing characteristics of secondary miRNAs as master regulators within a diverse set of differentially expressed genes is the absence of direct target mRNA for them. Instead, these master regulators exclusively govern the regulation of miRNAs that target specific mRNAs. Through in silico analysis, we identified 18 miRNAs among 385 differentially expressed miRNAs (DEmiRNAs) with no direct target mRNAs among 58 differentially expressed mRNAs (DEmRNAs) in peripheral blood of patients with myocardial infarction (MI). Instead, these secondary miRNAs targeted 9 primary miRNAs that had 36 direct targets among 58 DEmRNAs. We found that one primary miRNA might be regulated by more than one secondary miRNAs and each secondary miRNA can target more than one primary miRNAs. Among identified miRNA-miRNA-mRNA networks miR-188-5p/miR-299-3p/natural killer cell granule protein (NKG7), miR-200a-3p/miR-199b-5p/granzyme B (GZMB), and miR-377-3p/miR-581/oviductal glycoprotein 1 (OVGP1) exhibited higher scors in terms of expression levels (>2-fold increase or decrease) and strengh of interactions (Delta G < -5). Given the extensive network of miRNA interactions, focusing on master regulators opens up avenues for identifying key regulatory nodes for more effective therapeutic strategies.