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Analysis of microRNA expression profiles and prediction of target gene signaling pathways in familial hypertrophic cardiomyopathy with myosin-binding protein C3 (MYBPC3) gene mutations

ABSTRACT: We investigated the role of microRNA (miRNAs) in familial hypertrophic cardiomyopathy (FHCM) with MYBPC3 gene mutations. We investigated the miRNAs expression profile in three patients with FHCM with MYBPC3 gene mutations and compared the miRNA expression profiles with those of the normal control group by miRNA-seq. The significantly differentially expressed miRNAs was verified by real-time polymerase chain reaction (PCR). Target genes and signaling pathways of the identified differentially expressed miRNAs were predicted by bioinformatics analysis. The three probands were all hypertrophic obstructive cardiomyopathy with severe myocardial hypertrophy, and two of the families had a family history of sudden cardiac death, representing a “malignant” phenotype. A total of 33 significantly differentially expressed miRNAs were detected in the peripheral blood of the three probands, of which 28 were upregulated and 5 were downregulated. Real-time PCR confirmed that the expression of miR-208b-3p was consistent with the microarray results, and the difference was statistically significant (P＜0.05). Bioinformatics analysis showed that miR-208b-3p was mainly enriched in 79 target genes including Dally, Frizzled, Dvl, Nlk, Stbm and CaMKII, and gene ontology (GO) analysis of target genes showed that miR-208b was mainly involved in the processes of growth cone, phosphoprotein phosphatase activity, and postsynapse organization. Kyoto encyclopedia of genes and genomes (KEGG) analysis revealed that the target genes regulated by miR-208b-3p were mainly involved in Wnt signaling pathway. These findings show the existence of a specific expression profile of miRNAs in patients with FHCM with MYBPC3 gene mutations, in which miR-208b-3p is significantly elevated, and is implicated as a regulator of cardiac hypertrophy. In addition, our results indicate that miRNA-208b-3p activates the Wnt signaling pathway through its target gene to promote cardiac hypertrophy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150078 | GEO | 2021/05/08

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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Analysis of microRNA expression profiles and prediction of target gene signaling pathways in familial hypertrophic cardiomyopathy with myosin-binding protein C3 (MYBPC3) gene mutations

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