Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcript expression levels of neonatal mouse cardiomyocytes mock-transfected, or transfected with cel-miR-67, hsa-miR-590-3p or hsa-miR-199a-3p

ABSTRACT: To identify the relevant targets of the selected miRNAs, we assessed global transcriptome changes by deep-sequencing total neonatal mouse cardiomyocyte RNA after transfection with hsa-miR-590-3p or hsa-miR-199a-3p Four condition experiment; one replicate per condition; mouse neonatal cardiomyocytes transfected with cel-miR-67, hsa-miR-590-3p and hsa-miR-199a-3p; samples collected 72 hours after transfection

ORGANISM(S): Mus musculus

SUBMITTER: Miguel Mano

PROVIDER: E-GEOD-41538 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Functional screening identifies miRNAs inducing cardiac regeneration.

Eulalio Ana A Mano Miguel M Dal Ferro Matteo M Zentilin Lorena L Sinagra Gianfranco G Zacchigna Serena S Giacca Mauro M

Nature 20121205 7429

In mammals, enlargement of the heart during embryonic development is primarily dependent on the increase in cardiomyocyte numbers. Shortly after birth, however, cardiomyocytes stop proliferating and further growth of the myocardium occurs through hypertrophic enlargement of the existing myocytes. As a consequence of the minimal renewal of cardiomyocytes during adult life, repair of cardiac damage through myocardial regeneration is very limited. Here we show that the exogenous administration of s ...[more]

PMID: 23222520

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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.

Dataset Information

Transcript expression levels of neonatal mouse cardiomyocytes mock-transfected, or transfected with cel-miR-67, hsa-miR-590-3p or hsa-miR-199a-3p

Publications

Functional screening identifies miRNAs inducing cardiac regeneration.

Similar Datasets

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