MicroRNA-663 prevents monocrotaline-induced pulmonary arterial hypertension by targeting TGF-β1/smad2/3 signaling. (December 2021)

• Record Type: Journal Article
• Authors: Li, Pan; Song, Jingwen; Du, He; Lu, Yuwen; Dong, Shaohua; Zhou, Siwei; Guo, Zhifu; Wu, Hong; Zhao, Xianxian; Qin, Yongwen; Zhu, Ni
• Is Part Of: Journal of molecular and cellular cardiology. Volume 161(2021)
• Page Start: 9
• Page End: 22
• Publication Date: 2021-12
• Subjects: miR-663 -- TGF-β1 -- Pulmonary artery smooth muscle cell -- Pulmonary vascular remodeling -- Pulmonary arterial hypertension; PAH Pulmonary Arterial Hypertension -- MCT Monocrotaline -- PASMCs Pulmonary Artery Smooth Muscle Cells -- PAECs Pulmonary Artery Endothelial Cells -- PDGF Platelet Derived Growth Factor -- TGF-β1 Transforming Growth Factor β1 -- EGF Epithelial Growth Factor -- RUNX2 Runt-related Transcription Factor 2 -- BMPR2 Bone Morphogenic Protein Receptor Type 2 -- CHD Congenital Heart Disease -- VEGF Vascular Endothelial Growth Factor -- ATF4 Activating Transcription Factor 4 -- PCNA Proliferating Cell Nuclear Antigen -- ISH In Situ Hybridization -- SMCGS Smooth Muscle Cell Growth Supplement -- qRT-PCR Quantitative Reverse Transcription Polymerase Chain Reaction -- H&E Hematoxylin and Eosin -- ELISA Enzyme-Linked Immunosorbent Assay -- IHC Immunohistochemistry; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2021.07.010
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Objective: Pulmonary vascular remodeling due to excessive growth factor production and pulmonary artery smooth muscle cells (PASMCs) proliferation is the hallmark feature of pulmonary arterial hypertension (PAH). Recent studies suggest that miR-663 is a potent modulator for tumorigenesis and atherosclerosis. However, whether miR-663 involves in pulmonary vascular remodeling is still unclear. Methods and results: By using quantitative RT-PCR, we found that miR-663 was highly expressed in normal human PASMCs. In contrast, circulating level of miR-663 dramatically reduced in PAH patients. In addition, in situ hybridization showed that expression of miR-663 was decreased in pulmonary vasculature of PAH patients. Furthermore, MTT and cell scratch-wound assay showed that transfection of miR-663 mimics significantly inhibited platelet derived growth factor (PDGF)-induced PASMCs proliferation and migration, while knockdown of miR-663 expression enhanced these effects. Mechanistically, dual-luciferase reporter assay revealed that miR-663 directly targets the 3'UTR of TGF-β1. Moreover, western blots and ELISA results showed that miR-663 decreased PDGF-induced TGF-β1 expression and secretion, which in turn suppressed the downstream smad2/3 phosphorylation and collagen I expression. Finally, intratracheal instillation of adeno-miR-663 efficiently inhibited the development of pulmonary vascular remodeling and right ventricular hypertrophy in monocrotaline (MCT)-induced PAH rat models. Conclusion: These results indicate that miR-663 is a potential biomarker for PAH. MiR-663 decreases PDGF-BB-induced PASMCs proliferation and prevents pulmonary vascular remodeling and right ventricular hypertrophy in MCT-PAH by targeting TGF-β1/smad2/3 signaling. These findings suggest that miR-663 may represent as an attractive approach for the diagnosis and treatment for PAH. Graphical abstract: Unlabelled Image Highlights: miR-663 is reduced in plasma and pulmonary vessels of pulmonary hypertension patients. miR-663 targets TGF-β1/smad2/3 signaling and inhibits pulmonary arterial remodeling. miR-663 prevents the development of pulmonary hypertension.