title: Identifying microRNAs targeting Wnt/β-catenin pathway in end-stage idiopathic pulmonary arterial hypertension.
abstract: 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.
  
  
  
  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.
authors.affiliation: Department of Cardiopulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.|Division of Allergy and Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Danchen
authors.initials: D
authors.lastname: Wu
authors.affiliation: JHMI Deep Sequencing and Microarray Core, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: C Conover
authors.initials: CC
authors.lastname: Talbot
authors.affiliation: Division of Allergy and Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Cardiopulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.|State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China.
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Jing
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Damico
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA.
authors.forename: Rubin
authors.initials: R
authors.lastname: Tuder
authors.affiliation: Division of Allergy and Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hassoun
authors.affiliation: Division of Allergy and Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. lgao2@jhmi.edu.|The Johns Hopkins Asthma & Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD, 21224, USA. lgao2@jhmi.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Gao
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D015687:Cell Hypoxia; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension / Q000175:diagnosis / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D053263:Gene Regulatory Networks; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D034622:RNA Interference; D012372:ROC Curve; D060449:Wnt Signaling Pathway
chemical_list: D015415:Biomarkers; D035683:MicroRNAs
keywords: Idiopathic pulmonary arterial hypertension; MicroRNA; Microarray; Wnt/β-catenin