title: miR-29a-3p attenuates hypoxic pulmonary hypertension by inhibiting pulmonary adventitial fibroblast activation.
abstract: Activation of pulmonary adventitial fibroblasts plays a key role in the pulmonary vascular remodeling in hypoxic pulmonary hypertension. Previous studies showed that miRNAs participated in the regulation of fibroblast activation. This study explored the role of miR-29 in the activation of pulmonary adventitial fibroblasts and the therapeutic potential in hypoxic pulmonary hypertension. We found that hypoxia-induced pulmonary adventitial fibroblasts activation was accompanied with a drastic decrease of miR-29a-3p expression. Knockdown of hypoxia-inducible factor-1 α or Smad3 reversed the hypoxia-induced decrease of miR-29-3p in cultured pulmonary adventitial fibroblasts. In vitro, miR-29a-3p mimic inhibited the hypoxia-induced proliferation, migration, and secretion of pulmonary adventitial fibroblasts, suppressed the hypoxia-induced expression of α-smooth muscle actin and extracellular matrix collagen in pulmonary adventitial fibroblasts; however, miR-29a-3p inhibitor mimicked the effect of hypoxia on the activation of pulmonary adventitial fibroblasts. Further studies revealed that preventative or therapeutic administration of miR-29a-3p significantly decreased pulmonary artery pressure and right ventricle hypertrophy index and ameliorated pulmonary vascular remodeling in hypoxic pulmonary hypertension rats. These findings suggest that miR-29a-3p regulates the activation and phenotype of pulmonary adventitial fibroblasts in hypoxia and has preventative and therapeutic potential in hypoxic pulmonary hypertension.
authors.affiliation: From the Department of Pathology, Xijing Hospital (Y.L., M.-Q.D., Z.-C.L.), Department of Pathology and Pathophysiology (Y.L, H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), Lung Injury and Repair Center (Y.L., H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), and Department of Respiratory, Xijing Hospital (Z.F.), Fourth Military Medical University, Xi'an, People's Republic of China; and Department of Pathophysiology and High Altitude Physiology, Third Military Medical University, Chongqing, China (Y.-Q.G.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Luo
authors.affiliation: From the Department of Pathology, Xijing Hospital (Y.L., M.-Q.D., Z.-C.L.), Department of Pathology and Pathophysiology (Y.L, H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), Lung Injury and Repair Center (Y.L., H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), and Department of Respiratory, Xijing Hospital (Z.F.), Fourth Military Medical University, Xi'an, People's Republic of China; and Department of Pathophysiology and High Altitude Physiology, Third Military Medical University, Chongqing, China (Y.-Q.G.).
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Dong
authors.affiliation: From the Department of Pathology, Xijing Hospital (Y.L., M.-Q.D., Z.-C.L.), Department of Pathology and Pathophysiology (Y.L, H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), Lung Injury and Repair Center (Y.L., H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), and Department of Respiratory, Xijing Hospital (Z.F.), Fourth Military Medical University, Xi'an, People's Republic of China; and Department of Pathophysiology and High Altitude Physiology, Third Military Medical University, Chongqing, China (Y.-Q.G.).
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: From the Department of Pathology, Xijing Hospital (Y.L., M.-Q.D., Z.-C.L.), Department of Pathology and Pathophysiology (Y.L, H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), Lung Injury and Repair Center (Y.L., H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), and Department of Respiratory, Xijing Hospital (Z.F.), Fourth Military Medical University, Xi'an, People's Republic of China; and Department of Pathophysiology and High Altitude Physiology, Third Military Medical University, Chongqing, China (Y.-Q.G.).
authors.forename: Zhao
authors.initials: Z
authors.lastname: Feng
authors.affiliation: From the Department of Pathology, Xijing Hospital (Y.L., M.-Q.D., Z.-C.L.), Department of Pathology and Pathophysiology (Y.L, H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), Lung Injury and Repair Center (Y.L., H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), and Department of Respiratory, Xijing Hospital (Z.F.), Fourth Military Medical University, Xi'an, People's Republic of China; and Department of Pathophysiology and High Altitude Physiology, Third Military Medical University, Chongqing, China (Y.-Q.G.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Department of Pathology, Xijing Hospital (Y.L., M.-Q.D., Z.-C.L.), Department of Pathology and Pathophysiology (Y.L, H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), Lung Injury and Repair Center (Y.L., H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), and Department of Respiratory, Xijing Hospital (Z.F.), Fourth Military Medical University, Xi'an, People's Republic of China; and Department of Pathophysiology and High Altitude Physiology, Third Military Medical University, Chongqing, China (Y.-Q.G.).
authors.forename: Yu-Qi
authors.initials: YQ
authors.lastname: Gao
authors.affiliation: From the Department of Pathology, Xijing Hospital (Y.L., M.-Q.D., Z.-C.L.), Department of Pathology and Pathophysiology (Y.L, H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), Lung Injury and Repair Center (Y.L., H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), and Department of Respiratory, Xijing Hospital (Z.F.), Fourth Military Medical University, Xi'an, People's Republic of China; and Department of Pathophysiology and High Altitude Physiology, Third Military Medical University, Chongqing, China (Y.-Q.G.). dongmqxh@fmmu.edu.cn lizhic@fmmu.edu.cn.
authors.forename: Ming-Qing
authors.initials: MQ
authors.lastname: Dong
authors.affiliation: From the Department of Pathology, Xijing Hospital (Y.L., M.-Q.D., Z.-C.L.), Department of Pathology and Pathophysiology (Y.L, H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), Lung Injury and Repair Center (Y.L., H.-Y.D., B.Z., Y.L., M.-Q.D., Z.-C.L.), and Department of Respiratory, Xijing Hospital (Z.F.), Fourth Military Medical University, Xi'an, People's Republic of China; and Department of Pathophysiology and High Altitude Physiology, Third Military Medical University, Chongqing, China (Y.-Q.G.). dongmqxh@fmmu.edu.cn lizhic@fmmu.edu.cn.
authors.forename: Zhi-Chao
authors.initials: ZC
authors.lastname: Li
mesh_terms: D063194:Adventitia / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000502:physiology; D008168:Lung / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology / Q000627:therapeutic use*; D008969:Molecular Sequence Data; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000502:physiology; D014162:Transfection; D066253:Vascular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D016326:Extracellular Matrix Proteins; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C526366:MIRN29 microRNA, rat; D035683:MicroRNAs; D051900:Smad3 Protein; C497787:Smad3 protein, rat
keywords: hypoxia; pulmonary hypertension