miR-21 regulates chronic hypoxia-induced pulmonary vascular remodeling.
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.
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama, Birmingham, USA.
Shanzhong
S
Yang
Sami
S
Banerjee
Andressa de
Ad
Freitas
Huachun
H
Cui
Na
N
Xie
Edward
E
Abraham
Gang
G
Liu
D056151:Airway Remodeling / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008168:Lung / Q000378:metabolism / Q000503:physiopathology*; D036961:Matrix Attachment Region Binding Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000503:physiopathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology*; D011651:Pulmonary Artery / Q000378:metabolism / Q000503:physiopathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
C494811:BCL2L1 protein, human; C530104:CCND1 protein, human; D018797:Cell Cycle Proteins; C531950:MIRN21 microRNA, mouse; D036961:Matrix Attachment Region Binding Proteins; D035683:MicroRNAs; C469541:Satb1 protein, mouse; D051020:bcl-X Protein; D019938:Cyclin D1; C510836:WWP1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II