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A novel system-level approach using RNA-sequencing data identifies miR-30-5p and miR-142a-5p as key regulators of apoptosis in myocardial infarction.

ABSTRACT: This study identified microRNAs involved in myocardial infarction (MI) through a novel system-level approach using RNA sequencing data in an MI mouse model. This approach involved the extraction of DEGs and DEmiRs from RNA-seq data in sham and MI samples and the subsequent selection of two miRNAs: miR-30-5p (family) and miR-142a-5p, which were downregulated and upregulated in MI, respectively. Gene Set Enrichment Analysis (GSEA) using the predicted targets of the two miRNAs suggested that apoptosis is an essential gene ontology (GO)-associated term. In vitro functional assays using neonatal rat ventricular myocytes (NRVMs) demonstrated that miR-30-5p is anti-apoptotic and miR-142a-5p is pro-apoptotic. Luciferase assays showed that the apoptotic genes, Picalm and Skil, and the anti-apoptotic genes, Ghr and Kitl, are direct targets of miR-30-5p and miR-142a-5p, respectively. siRNA studies verified the results of the luciferase assays for target validation. The results of the system-level high throughput approach identified a pair of functionally antagonistic miRNAs and their targets in MI. This study provides an in-depth analysis of the role of miRNAs in the pathogenesis of MI which could lead to the development of therapeutic tools. The system-level approach could be used to identify miRNAs involved in variety of other diseases.

SUBMITTER: Kim JO

PROVIDER: S-EPMC6168573 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A novel system-level approach using RNA-sequencing data identifies miR-30-5p and miR-142a-5p as key regulators of apoptosis in myocardial infarction.

Kim Jin Ock JO Park Jei Hyoung JH Kim Taeyong T Hong Seong Eui SE Lee Ji Young JY Nho Kyoung Jin KJ Cho Chunghee C Kim Yong Sook YS Kang Wan Seok WS Ahn Youngkeun Y Kim Do Han DH

Scientific reports 20181002 1

This study identified microRNAs involved in myocardial infarction (MI) through a novel system-level approach using RNA sequencing data in an MI mouse model. This approach involved the extraction of DEGs and DEmiRs from RNA-seq data in sham and MI samples and the subsequent selection of two miRNAs: miR-30-5p (family) and miR-142a-5p, which were downregulated and upregulated in MI, respectively. Gene Set Enrichment Analysis (GSEA) using the predicted targets of the two miRNAs suggested that apopto ...[more]

PMID: 30279543

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Project description:BackgroundThe strain parameters of Real-Time Three-Dimensional Spot Tracking Echocardiography (RT3D-STE) are GLS, GAS, GRS, and GCS, while each index can significantly diagnose Acute Myocardial Infarction (AMI) patients, but none of them can distinguish between NSTEMI and STEMI. MicroRNAs (miRNAs) play essential roles in Acute Myocardial Infarction (AMI), but little is known about the value of exosome miRNA combined with Real-Time Three-Dimensional Spot Tracking Echocardiography (RT3D-STE) between ST-segment Elevation Myocardial Infarction (STEMI) and Non-ST-segment Elevation Myocardial Infarction (NSTEMI).AimTo estimate the exosomal miRNAs related to strain parameters of RT3D-STE as biomarkers for early detection of STEMI and NSTEMI.MethodsThe present study collected plasma samples from thirty-four (34) patients with AMI (including STEMI and NSTEMI) and employed high-throughput sequence technology and real-time quantitative polymerase chain reaction (RT-qPCR) to identify the differentially expressed miRNAs. The Pearson correlation coefficient is used to measure the strength of a linear association between differentially expressed miRNAs and strain parameters of RT3D-STE.ResultsTwenty-eight (28) differentially expressed exosomal miRNAs were universally identified between STEMI, NSTEM, and normal groups. Among them, there are 10 miRNAs (miR-152-5p, miR-3681-5p, miR-193a-5p, miR-193b-5p miR-345-5p, miR-125a-5p, miR-365a-3p, miR-4520-2-3p, hsa-miR-193b-3p and hsa-miR-5579-5p) with a Pearson correlation greater than 0.6 with RT3D-STE strain parameters. Especially, miR-152-5p and miR-3681-5p showed the most significant correlation with RT3D-STE strain parameters. Target genes of these 10 miRNAs are analyzed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment, and they were found to be mainly involved in the cellular metabolism processes and HIF-1 signaling pathway. RT-qPCR verified the significant differential expression of miR-152-5p and miR-3681-5p between STEMI and NSTEM groups.ConclusionRT3D-STE and exosome miRNAs can be used as a hierarchical diagnostic system in AMI. If the RT3D-STE is abnormal, the exosome miRNAs can be detected again to obtain more detailed and accurate diagnostic results between STEMI and NSTEM groups. Exosomal miR-152-5p and miR-3681-5p may serve as potential biomarkers for ST-segment elevation myocardial infarction.

Project description:Myocardial infarction (MI), the globally leading cause of heart failure, morbidity and mortality, involves post-MI ventricular remodeling, a complex process including acute injury healing, scar formation and global changes in the surviving myocardium. The molecular mechanisms involved in adverse post-infarct left ventricular remodeling still remain poorly defined. Recently, microRNAs have been implicated in the development and progression of various cardiac diseases as crucial regulators of gene expression. We previously demonstrated that in a murine model of pressure overload, a model of heart failure secondary to aortic stenosis or chronic high blood pressure, elevated myocardial expression of miR-199b-5p is sufficient to activate calcineurin/NFAT signaling, leading to exaggerated cardiac pathological remodeling and dysfunction. Given the differences in left ventricular remodeling secondary to post-infarct healing and pressure overload, we evaluated miR-199b function in post-MI remodeling. We confirmed that the expression of miR-199b is elevated in the post-infarcted heart. Transgenic animals with cardiomyocyte-restricted overexpression of miR-199b-5p displayed exaggerated pathological remodeling after MI, reflected by severe systolic and diastolic dysfunction and fibrosis deposition. Conversely, therapeutic silencing of miR-199b-5p in MI-induced cardiac remodeling by using an antagomir to specifically inhibit endogenous miR-199b-5p in vivo, resulted in efficient suppression of cardiac miR-199b-5p expression and attenuated cardiac dysfunction and dilation following MI. Mechanistically, miR-199b-5p influenced the expression of three predicted target genes in post-infarcted hearts, dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1a), the notch1 receptor and its ligand jagged1. In conclusion, here we provide evidence supporting that stress-induced miR-199b-5p participates in post-infarct remodeling by simultaneous regulation of distinct target genes.

Project description:Myocardial infarction (MI) is the most prevalent cardiac disease with high mortality, leading to severe heart injury. Circular RNAs (circRNAs) are a new type of regulatory RNAs and participate in multiple pathological cardiac progressions. However, the role of circRNAs Postn (circPostn) in MI modulation remains unclear. Here, we aimed to explore the effect of circPostn on MI-induced myocardial injury and cardiac remodeling. We identified that the expression of circPostn was elevated in the plasma of MI patients, MI mouse model, and hypoxia and reoxygenation (H/R)-treated human cardiomyocytes. The depletion of circPostn significantly attenuated MI-related myocardium injury and reduced the infarct size in MI mouse model. The circPostn knockdown obviously enhanced left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS) and inhibited left ventricular anterior wall thickness at diastole (LVAWd) and left ventricular posterior wall thickness at diastole (LVPWd). The depletion of circPostn was able to decrease MI-induced expression of collagen 1α1 and collagen 3α1 in the ventricular tissues of mice. The protein expression of collagen and α-smooth muscle actin (SMA) was up-regulated in MI mice and was inhibited by circPostn knockdown. Meanwhile, the expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was repressed by circPostn depletion in the ventricular tissues of MI mice. Besides, the circPostn depletion attenuated cardiomyocyte apoptosis in mice. Mechanically, circPostn served as a miR-96-5p sponge and miR-96-5p-targeted BNIP3 in human cardiomyocytes, in which circPostn up-regulated BNIP3 expression by targeting miR-96-5p. circPostn promoted H/R-induced cardiomyocyte injury by modulating miR-96-5p/BNIP3 axis. Thus, we conclude that circPostn contributes to MI-induced myocardial injury and cardiac remodeling by regulating miR-96-5p/BNIP3 axis. Our finding provides new insight into the mechanism by which circPostn regulates MI-related cardiac dysfunction. circPostn, miR-96-5p, and BNIP3 are potential targets for the treatment of MI-caused heart injury.

Dataset Information

A novel system-level approach using RNA-sequencing data identifies miR-30-5p and miR-142a-5p as key regulators of apoptosis in myocardial infarction.

Publications

A novel system-level approach using RNA-sequencing data identifies miR-30-5p and miR-142a-5p as key regulators of apoptosis in myocardial infarction.

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