Adeno-associated virus-mediated delivery of anti-miR-199a tough decoys attenuates cardiac hypertrophy
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ABSTRACT:
PROVIDER: PRJNA650214 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12366036_1.fastq.gz | Fastqsanger.gz | |||
| SRR12366036_2.fastq.gz | Fastqsanger.gz | |||
| SRR12366037_1.fastq.gz | Fastqsanger.gz | |||
| SRR12366037_2.fastq.gz | Fastqsanger.gz | |||
| SRR12366038_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
2020-12-31 | GSE155545 | GEO
Project description:MicroRNAs (miRNAs) are important regulators in the process of cardiac hypertrophy and heart failure. Previous studies have shown that miR-199a is upregulated in pressure-overload cardiac hypertrophy and that inhibition of miR-199a attenuates cardiac hypertrophy in vitro. However, the therapeutic role of anti-miR-199a treatment in the cardiac hypertrophy in vivo model is less known. Here, we show an efficient and useful method to treat mouse cardiac hypertrophy and restore cardiac function through injection of adeno-associated virus (AAV)-mediated anti-miR-199a tough decoys (TuDs). RNA-seq transcriptome analysis indicated that genes related to cytoplasmic translation and mitochondrial respiratory chain complex assembly were upregulated in anti-miR-199a-treated recovered hearts. We further validated that PGC-1α is the direct target of miR-199a involved in the therapeutic effect and the regulation of the PGC-1α/ERRα axis and that the downstream pathway of mitochondrial fatty acid oxidation and oxidative phosphorylation constitute the underlying mechanism of the restored mitochondrial structure and function in our anti-miR-199a-treated mice. Our study highlights the important regulatory role of miR-199a in cardiac hypertrophy and the value of the AAV-mediated miRNA delivery system.
| S-EPMC7787996 | biostudies-literature
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.
2024-01-26 | PXD042904 | Pride
Project description:To assess the impact of miR-199a-5p silencing on lung fibrogenesis, LNA-miR-199a-5p (5mg/kg) or control formulated for in vivo delivery was instilled intratracheally 4 days and 2 days before intratracheal administration of bleomycin (1 unit/kg) or PBS as well as 4 days after bleomycin or PBS treatment.
2019-04-11 | GSE97825 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal pulmonary disorder characterized by fibroblast proliferation and the excess deposit of extracellular matrix proteins. The etiology of IPF is unknown, but a central role for microRNAs (miRNAs), a class of small non-coding regulatory RNAs, has been recently suggested. We report the upregulation of miR-199a-5p in mouse lungs undergoing bleomycin-induced fibrosis and also in human biopsies from IPF patients. Levels of miR-199a-5p were increased selectively in myofibroblasts and putative profibrotic effects of miR-199a-5p were further investigated in cultured lung fibroblasts. MiR-199a-5p expression was induced upon TGFβ exposure and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts. CAV1, a critical mediator of pulmonary fibrosis, was established as a bona fide target of miR-199a-5p. Finally, we also found an aberrant expression of miR-199a-5p in mouse models of kidney and liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. We propose miR-199a-5p as a major regulator of fibrosis that represents a potential therapeutic target to treat fibroproliferative diseases. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-02-01 | E-GEOD-34818 | biostudies-arrayexpress
Project description:miR-199a expression was enforced in HMLE cells using lentiviral vector pLEX. The transcriptome profiles changes following miR-199a expression was studied.
2017-05-05 | GSE85629 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal pulmonary disorder characterized by fibroblast proliferation and the excess deposit of extracellular matrix proteins. The etiology of IPF is unknown, but a central role for microRNAs (miRNAs), a class of small non-coding regulatory RNAs, has been recently suggested. We report the upregulation of miR-199a-5p in mouse lungs undergoing bleomycin-induced fibrosis and also in human biopsies from IPF patients. Levels of miR-199a-5p were increased selectively in myofibroblasts and putative profibrotic effects of miR-199a-5p were further investigated in cultured lung fibroblasts. MiR-199a-5p expression was induced upon TGFβ exposure and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts. CAV1, a critical mediator of pulmonary fibrosis, was established as a bona fide target of miR-199a-5p. Finally, we also found an aberrant expression of miR-199a-5p in mouse models of kidney and liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. We propose miR-199a-5p as a major regulator of fibrosis that represents a potential therapeutic target to treat fibroproliferative diseases. This SuperSeries is composed of the SubSeries listed below.
2013-02-01 | GSE34818 | GEO
Project description:Trastuzumab improves overall survival for HER2+ breast cancer, but its short half-life in the cerebral spinal fluid (~2-4 days) and delivery limitations restrict the ability to target HER2+ central nervous system (CNS) disease.We developed an adeno-associated virus (AAV) vector expressing a codon-optimized, ubiquitin C (UbC)-promoter-driven trastuzumab sequence (AAV9.UbC.trastuzumab) for intrathecal administration. Transgene expression was evaluated in adult Rag1 knockout mice and rhesus nonhuman primates (NHPs) after a single intracerebroventricular (ICV) or intra-cisterna magna (ICM) AAV9.UbC.trastuzumab injection, respectively, using real-time PCR, ELISA, Western blot, in situ hybridization, single-nucleus RNA sequencing, and liquid chromatography-mass spectrometry; antitumor efficacy was evaluated in brain xenografts using HER2+ breast cancer cell lines (BT-474, MDA-MB-453).Transgene expression was detected in brain homogenates of Rag1 knockout mice following a single ICV injection of AAV9.UbC.trastuzumab (1×1011 vector genome copies [GC]/mouse) and tumor progression was inhibited in xenograft models of breast-to-brain metastasis. In NHPs, ICM delivery of AAV9.UbC.trastuzumab (3×1013 GC/animal) was well tolerated (36–37 days in-life) and resulted in transgene expression in CNS tissues and cerebrospinal fluid at levels sufficient to induce complete tumor remission in MDA-MB-453 brain xenografts. With AAV9’s proven clinical safety record, this gene therapy may represent a viable approach for targeting HER2+ CNS malignancies.
2024-02-05 | GSE255027 | GEO
Project description:Natural and synthetic circular RNAs effectively impair miRNA function. MiR-21-5p is a potent oncomiR presenting ~33% of all miRNAs across cancers, ~41% in lung adenocarcinoma (LUAD), and ~68% in LUAD-derived cells. We validate and identify five main tumor suppressors targeted by miR-21-5p by deletion of the MIR21 locus in LUAD cells. Synthetic, liposome-delivered circular miR-21-5p decoys enhance expression of these tumor suppressors and severely impair tumor cell vitality at low doses. Decoy efficacy is not increased by bulging of miR-21-5p targeting sites, but associated with substantial cellular decoy stability, indicated by a half-life of ~20h. The intraperitoneal application of nanoparticle-delivered miR-21-5p decoys significantly impairs tumor growth in mouse LUAD tumor models. Decoys are well tolerated and were enriched in lung tissue. However, despite low decoy abundance, tumor suppressor expression was only increased in subcutaneous tumors. These findings suggest nanoparticle-delivered circular miRNA decoys as potent therapeutics in cancer treatment.
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Project description:We found that miR-199a-3p expression is decreased in cSCC biopsies and cell lines compared to normal skin biopsies or normal keratinocytes cell. To understand the role lost expression of miR-199a-3p might have in tumorigenesis of keratinocytes, we aimed to fine possible biochemical pathways and possible targets of miR-199a-3p in cSCC. In order do so, we overexpressed miR-199a-3p in cSCC and used microarrays to find global gene expression affected by miR-199a-3p.
2022-11-01 | GSE186031 | GEO