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Published on: June 15, 2018
Identifying microRNAs targeting Wnt/β-catenin pathway in end-stage idiopathic pulmonary arterial hypertension
Danchen Wu1,2, C Conover Talbot3, Qun Liu2
1Department of Cardiopulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Unlabelled:
MicroRNAs (miRNAs) play important roles in the pathogenesis of pulmonary arterial hypertension (PAH). However, the pathways targeted by miRNAs in PAH have not been systematically investigated. We aim to identify dysregulated miRNAs for patients with idiopathic PAH (IPAH). miRNA profiling was performed on lung tissue total RNA from eight IPAH patients and eight control subjects. Real-time quantitative RT-PCR (qRT-PCR) was used for validation of miRNA and mRNA expression levels in 14 IPAH patients and 14 control subjects. Pathway enrichment analysis showed that Wnt/β-catenin signaling is among the top PAH-related pathways enriched in target genes of dysregulated miRNAs. We confirmed the significant increased expression levels of five miRNAs (let-7a-5p, miR-26b-5p, miR-27b-3p, miR-199a-3p and miR-656) targeting major PAH-related pathways. Moreover, qRT-PCR validation of Wnt/β-catenin pathway activation indicated multiple genes including receptors (FZD4, FZD5), core molecule (CTNNB1), and downstream targets (CCND1, VEGFA, and AXIN2) were significantly upregulated. The expression level of miR-199b-5p was positively correlated with patients' hemodynamics (PVR: r = 0.522, p = 0.038) and pulmonary vascular remodeling (muscularization: r = 0.540, p = 0.021). We confirmed overexpression of miR-199b-5p in hypoxic pulmonary arterial endothelial cells that negatively regulates GSK3B expression. In summary, miRNAs influence the pathogenesis of PAH by regulating major PAH-related pathways including Wnt/β-catenin in end-stage IPAH.
Key Message:
It is the first miRNA profiling study in lung tissue from end-stage idiopathic PAH. We identified dysregulated miRNAs and major pathways (e.g., Wnt signaling) in IPAH. Levels of miRNA expression were correlated with hemodynamics and pathological changes. We observed aberrant expression of target genes in the Wnt/β-catenin pathway. miRNAs influence the pathogenesis of PAH by regulating major PAH-related pathways.
Insights
MicroRNAs (miRNAs) are implicated in pulmonary arterial hypertension (PAH) pathogenesis. This study identifies dysregulated miRNAs and highlights the Wnt/β-catenin pathway
Area of Science:
- Molecular Biology
- Genetics
- Cardiovascular Research
Background:
- MicroRNAs (miRNAs) are key regulators of gene expression.
- Pulmonary arterial hypertension (PAH) involves complex molecularpathways.
- The specific roles of miRNAs in PAH pathogenesis remain incompletely understood.
Purpose of the Study:
- To identify dysregulated miRNAs in idiopathic PAH (IPAH).
- To investigate the pathways targeted by these miRNAs in IPAH.
- To explore the correlation between miRNA expression, disease severity, and pathological changes.
Main Methods:
- miRNA profiling of lung tissue from IPAH patients and controls.
- Quantitative reverse transcription polymerase chain reaction (qRT-PCR) for miRNA and mRNA validation.
- Pathway enrichment analysis to identify targeted signaling pathways.
- Correlation analysis between miRNA expression and clinical/pathological parameters.
Main Results:
- Several miRNAs, including let-7a-5p, miR-26b-5p, miR-27b-3p, miR-199a-3p, and miR-656, were significantly upregulated in IPAH.
- The Wnt/β-catenin signaling pathway was identified as a major pathway targeted by dysregulated miRNAs.
- Expression of Wnt/β-catenin pathway genes (e.g., FZD4, FZD5, CTNNB1, CCND1, VEGFA, AXIN2) was significantly upregulated.
- miR-199b-5p expression correlated positively with pulmonary vascular resistance and vascular remodeling.
- Overexpression of miR-199b-5p was confirmed in hypoxic pulmonary arterial endothelial cells, negatively regulating GSK3B.
Conclusions:
- Dysregulated miRNAs, particularly those targeting the Wnt/β-catenin pathway, contribute to IPAH pathogenesis.
- miRNA expression levels correlate with disease severity and pathological features in IPAH.
- Targeting miRNA-regulated pathways may offer novel therapeutic strategies for PAH.
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