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Adeno-associated virus-mediated delivery of anti-miR-199a tough decoys attenuates cardiac hypertrophy

ABSTRACT: MicroRNAs (miRNAs) are important regulators in the process of cardiac hypertrophy and heart failure. Previous studies showed that miR-199a is upregulated in pressure-overload cardiac hypertrophy and overexpression of miR-199a induces cardiac hypertrophy in vivo. However, the therapeutic role of anti-miR-199a treatment in cardiac hypertrophy is of little known. Here, we showed a novel and effective way to treat mice cardiac hypertrophy and restored cardiac function through injection of adeno-associated virus (AAV) which expressed anti-miR-199a tough decoys (TuDs). We performed the RNA-seq profiling in both AAV9-EGFP control and AAV9-anti-miR-199a TuDs injected cardiac hypertrophic mice. The transcriptome analysis indicates that genes related to cytoplasmic translation, mitochondrial respiratory chain complex assembly were upregulated by anti-miR-199a treated recovered hearts.

ORGANISM(S): Mus musculus

PROVIDER: GSE155545 | GEO | 2020/12/31

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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Adeno-associated virus-mediated delivery of anti-miR-199a tough decoys attenuates cardiac hypertrophy

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