Abstract
Chronic hypoxia causes pulmonary vascular remodeling leading to pulmonary hypertension (PH) and right ventricle (RV) hypertrophy. Aberrant expression of microRNA (miRNA) is closely associated with a number of pathophysiologic processes. However, the role of miRNAs in chronic hypoxia-induced pulmonary vascular remodeling and PH has not been well characterized. In this study, we found increased expression of miR-21 in distal small arteries in the lungs of hypoxia-exposed mice. Putative miR-21 targets, including bone morphogenetic protein receptor (BMPR2), WWP1, SATB1, and YOD1, were downregulated in the lungs of hypoxia-exposed mice and in human pulmonary artery smooth muscle cells (PASMCs) overexpressing miR-21. We found that sequestration of miR-21, either before or after hypoxia exposure, diminished chronic hypoxia-induced PH and attenuated hypoxia-induced pulmonary vascular remodeling, likely through relieving the suppressed expression of miR-21 targets in the lungs of hypoxia-exposed mice. Overexpression of miR-21 enhanced, whereas downregulation of miR-21 diminished, the proliferation of human PASMCs in vitro and the expression of cell proliferation associated proteins, such as proliferating cell nuclear antigen, cyclin D1, and Bcl-xL. Our data suggest that miR-21 plays an important role in the pathogenesis of chronic hypoxia-induced pulmonary vascular remodeling and also suggest that miR-21 is a potential target for novel therapeutics to treat chronic hypoxia associated pulmonary diseases.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Airway Remodeling / genetics
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Airway Remodeling / physiology*
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Animals
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Apoptosis / genetics
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Bone Morphogenetic Protein Receptors, Type II / genetics
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Bone Morphogenetic Protein Receptors, Type II / metabolism
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Cell Cycle Proteins / genetics
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Cell Line
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Cell Proliferation
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Down-Regulation / genetics
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Humans
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Hypertension, Pulmonary / etiology
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Hypertension, Pulmonary / genetics
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Hypertension, Pulmonary / metabolism
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Hypertension, Pulmonary / physiopathology
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Hypertrophy, Right Ventricular / genetics
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Hypertrophy, Right Ventricular / metabolism
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Hypertrophy, Right Ventricular / physiopathology
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Hypoxia / complications
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Hypoxia / genetics
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Hypoxia / metabolism
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Hypoxia / physiopathology*
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Lung / metabolism
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Lung / physiopathology*
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Matrix Attachment Region Binding Proteins / genetics
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Matrix Attachment Region Binding Proteins / metabolism
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Mice
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MicroRNAs / genetics*
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Muscle, Smooth, Vascular / metabolism
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Muscle, Smooth, Vascular / physiopathology*
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Myocytes, Smooth Muscle / metabolism
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Myocytes, Smooth Muscle / pathology*
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Pulmonary Artery / metabolism
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Pulmonary Artery / physiopathology
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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Up-Regulation / genetics
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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BCL2L1 protein, human
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CCND1 protein, human
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Cell Cycle Proteins
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MIRN21 microRNA, mouse
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Matrix Attachment Region Binding Proteins
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MicroRNAs
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Satb1 protein, mouse
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bcl-X Protein
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Cyclin D1
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WWP1 protein, mouse
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Ubiquitin-Protein Ligases
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Bmpr2 protein, mouse
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Bone Morphogenetic Protein Receptors, Type II