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Bioinformatics prediction and experimental verification of a novel microRNA for myocardial fibrosis after myocardial infarction in rats

ABSTRACT: MicroRNAs (miRNAs) are a class of highly conserved endogenous noncoding single-stranded small RNAs with a length of 18-22 nucleotides. They are involved in regulation at the posttranscriptional and translational levels through the degradation and translation inhibition of messenger RNA (mRNA). It is estimated that at least 60% of all mammalian genes may be regulated by miRNAs. MiRNAs can help uncover the mechanisms of diseases and provide new entry points into therapy. Accumulated evidence has revealed that miRNAs are involved in the pathological process of cardiovascular disease through specific signaling pathways. To investigate the potential miRNAs for myocardial fibrosis post myocardial infarction, rat models of acute myocardial infarction (AMI) were established by ligating the anterior descending branch of the left coronary artery, while sham-operated rats were only threaded without ligation as a control group. There were three rats in each group. Thirteen differentially expressed miRNAs between the two groups were screened and their expression levels in the model group were all higher than those in the control group. The expression of miR-199a-5p was significantly increased in the model group in qRT-PCR, which was consistent with the results of the gene chip. KEGG enrichment analysis showed that the target genes of miR-199a-5p were enriched in the insulin signaling pathway. Furthermore, dual-luciferase reporter assay indicated that miR-199a-5p could negatively regulate the expression of GSK-3β. After transfection, the expression of miR-199a-5p was increased in the miR-199a-5p mimics group. The protein expression of GSK-3β was decreased in CFs transfected with miR-199a-5p mimics. In summary, our study identified miR-199a-5p could promote the progression of myocardial fibrosis after myocardial infarction by targeting GSK-3β, which provides novel targets for diagnosis and treatment of MF. In summary, our research suggests that miR-199a-5p promotes the progression of myocardial fibrosis after myocardial infarction through the activation of the insulin-PI3K/Akt-GSK-3β signaling pathway.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE208159 | GEO | 2022/07/14

REPOSITORIES: GEO

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Project description:Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder, characterized by cardiomyocyte hypertrophy, cardiomyocyte disarray and fibrosis, which has a prevalence of ~1:200-500 and predisposes individuals to sudden death and heart failure. The mechanisms through which diverse HCM-causing mutations cause cardiac dysfunction remain mostly unknown and their identification may reveal new therapeutic avenues. MicroRNAs have emerged as critical regulators of gene expression and disease phenotype in various pathologies. We explored whether miRNAs could play a role in HCM pathogenesis and offer potential therapeutic targets. Methods and Results: Using high-throughput miRNA expression profiling and qPCR analysis in two distinct mouse models of HCM, we found that miR-199a-3p expression levels are upregulated in mutant mice compared to age- and treatment-matched wild-type mice. We also found that miR-199a-3p expression is enriched in cardiac non-myocytes compared to cardiomyocytes. When we expressed miR-199a-3p mimic in cultured primary cardiac non-myocytes and analyzed the conditioned media by proteomics, we found that several ECM proteins (e.g., TSP2, FBLN3, COL11A1, LYOX) were differentially expressed. We confirmed our proteomics findings by qPCR analysis of selected mRNAs and demonstrated that miR-199a-3p mimic expression in cardiac non-myocytes drives upregulation of ECM genes including Tsp2, Fbln3, Pcoc1, Col1a1 and Col3a1. To examine the role of miR-199a-3p in vivo, we inhibited its function using lock-nucleic acid (LNA)-based inhibitors (antimiR-199a-3p) in an HCM mouse model. Our results revealed that progression of cardiac fibrosis is attenuated when miR-199a-3p function is inhibited in mild-to-moderate HCM. Finally, guided by computational target prediction algorithms, we identified mRNAs Cd151 and Itga3 as direct targets of miR-199a-3p and have shown that miR-199a-3p mimic expression negatively regulates AKT activation in cardiac non-myocytes. Conclusions: Altogether, our results suggest that miR-199a-3p may contribute to cardiac fibrosis in HCM through its actions in cardiac non-myocytes. Thus, inhibition of miR-199a-3p in mild-to-moderate HCM may offer therapeutic benefit in combination with complementary approaches that target the primary defect in cardiac myocytes.

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Bioinformatics prediction and experimental verification of a novel microRNA for myocardial fibrosis after myocardial infarction in rats

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