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In Vivo Nanovector Delivery of a Heart-specific MicroRNA-sponge
Published on: June 15, 2018
Role of miRNA-mRNA Interactome in Pathophysiology of Arrhythmogenic Cardiomyopathy
Fernando Bonet1, Oscar Campuzano2,3,4, José Córdoba-Caballero1,5
1Research Unit, Biomedical Research and Innovation Institute of Cadiz (INiBICA), Puerta del Mar University Hospital, 11009 Cádiz, Spain.
Insights
This study reveals novel microRNAs (miRNAs) involved in arrhythmogenic cardiomyopathy (ACM) pathogenesis. These findings offer potential new therapeutic targets for this inherited heart condition.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Disease Pathogenesis
Background:
- Arrhythmogenic cardiomyopathy (ACM) is an inherited heart condition causing ventricular arrhythmias and sudden cardiac death.
- Genetic variants in desmosome genes are primary causes, but molecular mechanisms remain unclear.
- Signaling pathways like Wnt/ß-catenin and TGF-β are implicated in ACM progression.
Purpose of the Study:
- To investigate the molecular pathophysiology of arrhythmogenic cardiomyopathy using transcriptomic analysis.
- To identify novel differentially expressed genes and microRNAs (miRNAs) in ACM hearts.
- To explore miRNA-mRNA interactions in ACM pathogenesis.
Main Methods:
- Analysis of mRNA and small RNA sequencing data from autopsied human hearts (ACM vs. healthy).
- Differential gene and miRNA expression analysis.
- Functional enrichment analysis and miRNA-mRNA interactome analysis.
Main Results:
- Identified 697 differentially expressed genes and 8 differentially expressed miRNAs in ACM hearts.
- Functional enrichment highlighted pathways related to mitochondrial respiration, oxidative stress, apoptosis, inflammation, and extracellular matrix.
- Discovered 11 negatively correlated miRNA-target pairs relevant to ACM.
Conclusions:
- Novel ACM-associated miRNAs with regulatory roles in disease pathogenesis were identified.
- These miRNAs represent potential key targets for future therapeutic strategies in arrhythmogenic cardiomyopathy.
- Understanding these molecular players advances knowledge of ACM pathophysiology.
Abstract:
Arrhythmogenic cardiomyopathy is an inherited entity characterized by irregular cell-cell adhesion, cardiomyocyte death and fibro-fatty replacement of ventricular myocytes, leading to malignant ventricular arrythmias, contractile dysfunction and sudden cardiac death. Pathogenic variants in genes that encode desmosome are the predominant cause of arrhythmogenic cardiomyopathy. Moreover, signalling pathways such as Wnt/ß-catenin and transforming growth factor-β have been involved in the disease progression. However, still little is known about the molecular pathophysiological mechanisms that underlie arrhythmogenic cardiomyopathy pathogenesis. We used mRNA and small RNA sequencing to analyse the transcriptome of health and arrhythmogenic cardiomyopathy of autopsied human hearts. Our results showed 697 differentially expressed genes and eight differentially expressed miRNAs. Functional enrichment revealed mitochondrial respiratory-related pathways, impaired response to oxidative stress, apoptotic signalling pathways and inflammatory response-related and extracellular matrix response pathways. Furthermore, analysis of the miRNA-mRNA interactome identified eleven negatively correlated miRNA-target pairs for arrhythmogenic cardiomyopathy. Our finding revealed novel arrhythmogenic cardiomyopathy-related miRNAs with important regulatory function in disease pathogenesis, highlighting their value as potential key targets for therapeutic approaches.
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