Down-regulation of miR-204 attenuates endothelial-mesenchymal transition by enhancing autophagy in hypoxia-induced pulmonary hypertension

Pulmonary arterial remodeling is a crucial cause of increased pulmonary artery pressure during pulmonary hypertension (PH). Recently, growing evidence has upheld the contribution of endothelial-mesenchymal transition (EndMT) to pulmonary arterial remodeling, but the underlying mechanisms remain larg...

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Bibliographic Details
Published in:European journal of pharmacology 2019-11, Vol.863, p.172673-172673, Article 172673
Main Authors: Liu, Ting, Zou, Xiao-Zhou, Huang, Ning, Ge, Xiao-Yue, Yao, Mao-Zhong, Liu, Hong, Zhang, Zheng, Hu, Chang-Ping
Format: Article
Language:English
Subjects:
3' Untranslated Regions - genetics
Animals
ATG7
Autophagy
Autophagy - genetics
Autophagy-Related Protein 7 - genetics
Cell Hypoxia - genetics
Cell Line
Down-Regulation
Endothelial-mesenchymal transition
Epithelial-Mesenchymal Transition - genetics
Humans
Hypertension, Pulmonary - genetics
Hypertension, Pulmonary - pathology
Male
MicroRNAs - genetics
miR-204
p62
Proteolysis
Pulmonary hypertension
Rats
Rats, Sprague-Dawley
Snail Family Transcription Factors - metabolism
Twist-Related Protein 1 - metabolism
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Summary:Pulmonary arterial remodeling is a crucial cause of increased pulmonary artery pressure during pulmonary hypertension (PH). Recently, growing evidence has upheld the contribution of endothelial-mesenchymal transition (EndMT) to pulmonary arterial remodeling, but the underlying mechanisms remain largely unaddressed. miR-204 has been implicated in PH, being anti-proliferative and pro-apoptotic in pulmonary artery smooth muscles cells (PASMCs), but its role in EndMT is still unknown. Here we found that miR-204 was down-regulated by hypoxia in rat pulmonary arterial intima and human pulmonary artery endothelial cells (HPAECs), and its further down-regulation by using miR-204 inhibitor suppressed hypoxia-induced EndMT. Moreover, autophagy, evoked by hypoxia in rat pulmonary arterial intima and HPAECs, suppressed hypoxia-induced EndMT via p62-dependent degradation of Snail and Twist. Additionally, autophagy was regulated by miR-204 targeting ATG7. While down-regulation of miR-204 in PASMCs reportedly promoted monocrotaline-induced pulmonary arterial hypertension via increased cell proliferation, our data suggested an important, albeit dichotomous, role of miR-204 down-regulation in endothelial cells in the process of EndMT that it attenuated EndMT by enhancing autophagy, thereby ameliorating hypoxia-induced PH to some extent.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2019.172673