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Endothelial Dec1-PPARγ Axis Impairs Proliferation and Apoptosis Homeostasis Under Hypoxia in Pulmonary Arterial Hypertension

Background: The hypoxia-induced pro-proliferative and anti-apoptotic characteristics of pulmonary arterial endothelial cells (PAECs) play critical roles in pulmonary vascular remodeling and contribute to hypoxic pulmonary arterial hypertension (PAH) pathogenesis. However, the mechanism underlying th...

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Autores principales: Li, Xiaoming, Liu, Chengcheng, Qi, Wenwen, Meng, Qiu, Zhao, Hui, Teng, Zhenxiao, Xu, Runtong, Wu, Xinhao, Zhu, Fangyuan, Qin, Yiming, Zhao, Miaoqing, Xu, Fenglei, Xia, Ming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576361/
https://www.ncbi.nlm.nih.gov/pubmed/34765605
http://dx.doi.org/10.3389/fcell.2021.757168
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author Li, Xiaoming
Liu, Chengcheng
Qi, Wenwen
Meng, Qiu
Zhao, Hui
Teng, Zhenxiao
Xu, Runtong
Wu, Xinhao
Zhu, Fangyuan
Qin, Yiming
Zhao, Miaoqing
Xu, Fenglei
Xia, Ming
author_facet Li, Xiaoming
Liu, Chengcheng
Qi, Wenwen
Meng, Qiu
Zhao, Hui
Teng, Zhenxiao
Xu, Runtong
Wu, Xinhao
Zhu, Fangyuan
Qin, Yiming
Zhao, Miaoqing
Xu, Fenglei
Xia, Ming
author_sort Li, Xiaoming
collection PubMed
description Background: The hypoxia-induced pro-proliferative and anti-apoptotic characteristics of pulmonary arterial endothelial cells (PAECs) play critical roles in pulmonary vascular remodeling and contribute to hypoxic pulmonary arterial hypertension (PAH) pathogenesis. However, the mechanism underlying this hypoxic disease has not been fully elucidated. Methods: Bioinformatics was adopted to screen out the key hypoxia-related genes in PAH. Gain- and loss-function assays were then performed to test the identified hypoxic pathways in vitro. Human PAECs were cultured under hypoxic (3% O(2)) or normoxic (21% O(2)) conditions. Hypoxia-induced changes in apoptosis and proliferation were determined by flow cytometry and Ki-67 immunofluorescence staining, respectively. Survival of the hypoxic cells was estimated by cell counting kit-8 assay. Expression alterations of the target hypoxia-related genes, cell cycle regulators, and apoptosis factors were investigated by Western blot. Results: According to the Gene Expression Omnibus dataset (GSE84538), differentiated embryo chondrocyte expressed gene 1-peroxisome proliferative-activated receptor-γ (Dec1-PPARγ) axis was defined as a key hypoxia-related signaling in PAH. A negative correlation was observed between Dec1 and PPARγ expression in patients with hypoxic PAH. In vitro observations revealed an increased proliferation and a decreased apoptosis in PAECs under hypoxia. Furthermore, hypoxic PAECs exhibited remarkable upregulation of Dec1 and downregulation of PPARγ. Dec1 was confirmed to be crucial for the imbalance of proliferation and apoptosis in hypoxic PAECs. Furthermore, the pro-surviving effect of hypoxic Dec1 was mediated through PPARγ inhibition. Conclusion: For the first time, Dec1-PPARγ axis was identified as a key determinant hypoxia-modifying signaling that is necessary for the imbalance between proliferation and apoptosis of PAECs. These novel endothelial signal transduction events may offer new diagnostic and therapeutic options for patients with hypoxic PAH.
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spelling pubmed-85763612021-11-10 Endothelial Dec1-PPARγ Axis Impairs Proliferation and Apoptosis Homeostasis Under Hypoxia in Pulmonary Arterial Hypertension Li, Xiaoming Liu, Chengcheng Qi, Wenwen Meng, Qiu Zhao, Hui Teng, Zhenxiao Xu, Runtong Wu, Xinhao Zhu, Fangyuan Qin, Yiming Zhao, Miaoqing Xu, Fenglei Xia, Ming Front Cell Dev Biol Cell and Developmental Biology Background: The hypoxia-induced pro-proliferative and anti-apoptotic characteristics of pulmonary arterial endothelial cells (PAECs) play critical roles in pulmonary vascular remodeling and contribute to hypoxic pulmonary arterial hypertension (PAH) pathogenesis. However, the mechanism underlying this hypoxic disease has not been fully elucidated. Methods: Bioinformatics was adopted to screen out the key hypoxia-related genes in PAH. Gain- and loss-function assays were then performed to test the identified hypoxic pathways in vitro. Human PAECs were cultured under hypoxic (3% O(2)) or normoxic (21% O(2)) conditions. Hypoxia-induced changes in apoptosis and proliferation were determined by flow cytometry and Ki-67 immunofluorescence staining, respectively. Survival of the hypoxic cells was estimated by cell counting kit-8 assay. Expression alterations of the target hypoxia-related genes, cell cycle regulators, and apoptosis factors were investigated by Western blot. Results: According to the Gene Expression Omnibus dataset (GSE84538), differentiated embryo chondrocyte expressed gene 1-peroxisome proliferative-activated receptor-γ (Dec1-PPARγ) axis was defined as a key hypoxia-related signaling in PAH. A negative correlation was observed between Dec1 and PPARγ expression in patients with hypoxic PAH. In vitro observations revealed an increased proliferation and a decreased apoptosis in PAECs under hypoxia. Furthermore, hypoxic PAECs exhibited remarkable upregulation of Dec1 and downregulation of PPARγ. Dec1 was confirmed to be crucial for the imbalance of proliferation and apoptosis in hypoxic PAECs. Furthermore, the pro-surviving effect of hypoxic Dec1 was mediated through PPARγ inhibition. Conclusion: For the first time, Dec1-PPARγ axis was identified as a key determinant hypoxia-modifying signaling that is necessary for the imbalance between proliferation and apoptosis of PAECs. These novel endothelial signal transduction events may offer new diagnostic and therapeutic options for patients with hypoxic PAH. Frontiers Media S.A. 2021-10-26 /pmc/articles/PMC8576361/ /pubmed/34765605 http://dx.doi.org/10.3389/fcell.2021.757168 Text en Copyright © 2021 Li, Liu, Qi, Meng, Zhao, Teng, Xu, Wu, Zhu, Qin, Zhao, Xu and Xia. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Li, Xiaoming
Liu, Chengcheng
Qi, Wenwen
Meng, Qiu
Zhao, Hui
Teng, Zhenxiao
Xu, Runtong
Wu, Xinhao
Zhu, Fangyuan
Qin, Yiming
Zhao, Miaoqing
Xu, Fenglei
Xia, Ming
Endothelial Dec1-PPARγ Axis Impairs Proliferation and Apoptosis Homeostasis Under Hypoxia in Pulmonary Arterial Hypertension
title Endothelial Dec1-PPARγ Axis Impairs Proliferation and Apoptosis Homeostasis Under Hypoxia in Pulmonary Arterial Hypertension
title_full Endothelial Dec1-PPARγ Axis Impairs Proliferation and Apoptosis Homeostasis Under Hypoxia in Pulmonary Arterial Hypertension
title_fullStr Endothelial Dec1-PPARγ Axis Impairs Proliferation and Apoptosis Homeostasis Under Hypoxia in Pulmonary Arterial Hypertension
title_full_unstemmed Endothelial Dec1-PPARγ Axis Impairs Proliferation and Apoptosis Homeostasis Under Hypoxia in Pulmonary Arterial Hypertension
title_short Endothelial Dec1-PPARγ Axis Impairs Proliferation and Apoptosis Homeostasis Under Hypoxia in Pulmonary Arterial Hypertension
title_sort endothelial dec1-pparγ axis impairs proliferation and apoptosis homeostasis under hypoxia in pulmonary arterial hypertension
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576361/
https://www.ncbi.nlm.nih.gov/pubmed/34765605
http://dx.doi.org/10.3389/fcell.2021.757168
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