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Published on: September 15, 2018
Regulation of SMAD Signaling Pathway by miRNAs Associated with Myocardial Fibrosis: In silico Analysis of Target Gene
Maria Pisklova1,2, German Osmak3,2, Olga Favorova3,2
1Chazov National Medical Research Center of Cardiology, Moscow, 121552, Russia. pisklova_maria@mail.ru.
Insights
MicroRNAs (miRNAs) are linked to hypertrophic cardiomyopathy (HCM) and myocardial fibrosis. This study identifies specific miRNAs regulating the TGF-β/SMAD pathway, crucial in HCM pathogenesis.
Area of Science:
- Cardiovascular Genetics
- Molecular Biology
- Biochemistry
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart condition.
- Myocardial fibrosis, heart failure, and arrhythmias are key features of HCM.
- Gene expression dysregulation, involving microRNAs (miRNAs), is implicated in HCM development.
Purpose of the Study:
- To investigate the role of miRNAs in myocardial fibrosis associated with HCM.
- To identify signaling pathways regulated by miRNAs involved in HCM pathogenesis.
- To explore the connection between miRNAs, fibrosis, and the TGF-β/SMAD pathway in HCM.
Main Methods:
- PubMed database search for miRNAs associated with myocardial fibrosis in HCM.
- In silico analysis using a developed algorithm to identify signaling pathways regulated by selected miRNAs.
- Bioinformatic identification of miRNA targets within the TGF-β/SMAD pathway.
Main Results:
- Fifteen miRNAs associated with myocardial fibrosis were identified.
- Ten of these miRNAs were found to regulate the TGF-β/SMAD signaling pathway.
- The MYC gene was identified as a major target of these miRNAs within the SMAD pathway.
- Previous research linked other miRNAs to TGF-β/SMAD pathway regulation in HCM-related hypertrophy.
Conclusions:
- The TGF-β/SMAD signaling pathway is a key regulator in the pathological processes of HCM.
- miRNAs play a significant role in regulating fibrosis and hypertrophy in HCM.
- Findings contribute to understanding the molecular mechanisms underlying HCM development.
Abstract:
Hypertrophic cardiomyopathy (HCM) is a hereditary heart disease caused by mutations in the sarcomere genes, which is accompanied by myocardial fibrosis leading to progressive heart failure and arrhythmias. Recent studies suggest that the HCM development involves dysregulation of gene expression. Among the molecules involved in this process are microRNAs (miRNAs), which are short non-coding RNAs. Typically, one miRNA regulates several target genes post-transcriptionally, hence, it might be difficult to determine the role of a particular miRNA in the disease pathogenesis. In this study, using the PubMed database, we selected 15 miRNAs whose expression is associated with myocardial fibrosis, one of the critical pathological processes in HCM. We then used an earlier developed algorithm to search in silico for the signaling pathways regulated by these miRNAs and found that ten of them participate in the regulation of the TGF-β/SMAD signaling pathway. At the same time, among the SMAD signaling pathway genes, the target of the most identified miRNAs was the MYC gene, which is involved in the development of fibrosis in some tissues. In our earlier work, we found that the TGF-β/SMAD pathway is also regulated by a set of other miRNAs associated with the myocardial hypertrophy in HCM. The fact that two sets of miRNAs identified in two independent bioinformatic studies are involved in the regulation of the same signaling pathway indicates that the SMAD signaling cascade is indeed a key element in the regulation of pathological processes in HCM. The obtained data might contribute to understanding pathological processes underlying HCM development.
