title: Differentially expressed plasma microRNAs and the potential regulatory function of Let-7b in chronic thromboembolic pulmonary hypertension.
abstract: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease characterized by misguided thrombolysis and remodeling of pulmonary arteries. MicroRNAs are small non-coding RNAs involved in multiple cell processes and functions. During CTEPH, circulating microRNA profile endued with characteristics of diseased cells could be identified as a biomarker, and might help in recognition of pathogenesis. Thus, in this study, we compared the differentially expressed microRNAs in plasma of CTEPH patients and healthy controls and investigated their potential functions. Microarray was used to identify microRNA expression profile and qRT-PCR for validation. The targets of differentially expressed microRNAs were identified in silico, and the Gene Ontology database and Kyoto Encyclopedia of Genes and Genomes pathway database were used for functional investigation of target gene profile. Targets of let-7b were validated by fluorescence reporter assay. Protein expression of target genes was determined by ELISA or western blotting. Cell migration was evaluated by wound healing assay. The results showed that 1) thirty five microRNAs were differentially expressed in CTEPH patients, among which, a signature of 17 microRNAs, which was shown to be related to the disease pathogenesis by in silico analysis, gave diagnostic efficacy of both sensitivity and specificity >0.9. 2) Let-7b, one of the down-regulated anti-oncogenic microRNAs in the signature, was validated to decrease to about 0.25 fold in CTEPH patients. 3) ET-1 and TGFBR1 were direct targets of let-7b. Altering let-7b level influenced ET-1 and TGFBR1 expression in pulmonary arterial endothelial cells (PAECs) as well as the migration of PAECs and pulmonary arterial smooth muscle cells (PASMCs). These results suggested that CTEPH patients had aberrant microRNA signature which might provide some clue for pathogenesis study and biomarker screening. Reduced let-7b might be involved in the pathogenesis of CTEPH by affecting ET-1 expression and the function of PAECs and PASMCs.
authors: Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P.R. China; Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing, P.R. China.
authors: Lijuan
authors: L
authors: Guo
authors: Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P.R. China; Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing, P.R. China.
authors: Yuanhua
authors: Y
authors: Yang
authors: Department of Physiology, Capital Medical University, Beijing, P.R. China.
authors: Jie
authors: J
authors: Liu
authors: Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P.R. China; Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing, P.R. China.
authors: Lei
authors: L
authors: Wang
authors: Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P.R. China; Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing, P.R. China.
authors: Jifeng
authors: J
authors: Li
authors: Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P.R. China.
authors: Ying
authors: Y
authors: Wang
authors: Department of Cardiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P.R. China.
authors: Yan
authors: Y
authors: Liu
authors: Department of Cardiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P.R. China.
authors: Song
authors: S
authors: Gu
authors: Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P.R. China; Beijing Institute of Heart, Lung and Vessel Disease, Capital Medical University, Beijing, P.R. China.
authors: Huili
authors: H
authors: Gan
authors: Department of Cardiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P.R. China.
authors: Jun
authors: J
authors: Cai
authors: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors: Jason X-J
authors: JX
authors: Yuan
authors: Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P.R. China; Department of Physiology, Capital Medical University, Beijing, P.R. China.
authors: Jun
authors: J
authors: Wang
authors: Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P.R. China; Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing, P.R. China; Department of Beijing Hospital, Ministry of Health, Beijing, P.R. China.
authors: Chen
authors: C
authors: Wang
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002465:Cell Movement; D002478:Cells, Cultured; D002908:Chronic Disease; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D011655:Pulmonary Embolism / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D019332:Endothelin-1; D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta; C487931:mirnlet7 microRNA, human; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human