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ITE promotes hypoxia‐induced transdifferentiation of human pulmonary arterial endothelial cells possibly by activating transforming growth factor‐β/Smads and MAPK/ERK pathways
Author(s) -
Wang Jinxia,
Yan Guosen,
Guo Haixu,
Zhu Ying,
Shui Xiaorong,
He Yuan,
Chen Can,
Lei Wei
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.29264
Subject(s) - transdifferentiation , mapk/erk pathway , transforming growth factor , microbiology and biotechnology , p38 mitogen activated protein kinases , runx2 , hypoxia (environmental) , chemistry , biology , signal transduction , osteoblast , stem cell , biochemistry , organic chemistry , oxygen , in vitro
This study aimed to investigate the transdifferentiation of human pulmonary arterial endothelial cells (HPAECs) into smooth muscle like (SM‐like) cells under hypoxic conditions and reveal the role of endogenous small molecular compound 2‐(1′ H ‐indole‐3′‐carbonyl)‐thiazole‐4‐carboxylicacid methyl ester (ITE) in this process. HPAECs were treated by hypoxia and hypoxia + ITE with different durations. The endothelial markers (CD31 and VE‐cad) and smooth muscle markers (α‐SMA, SM22α, and OPN) were investigated by immunofluorescence double staining, and their expressions, along with the differentiation regulators transforming growth factor‐β (TGF‐β) ligands and downstream signals including TGF‐β1, bone morphogenetic protein (BMP2), BMP9, Samd2/3, ERK, and p38 MAPK, were determined by Western blot analysis. The viability and proliferation of HPAECs were detected by Cell Counting Kit‐8 (CCK‐8) method and bromodeoxyuridine (BrdU) assays. As a result, hypoxia induced HPAECs transdifferentiation from paving‐stone‐like into polygonal or spindle cells, whose number increased greatly after additional ITE stimulation for 7 days. Compared with the normoxic HPAECs, the expression of endothelial markers reduced and smooth muscle markers were enhanced with the extension of hypoxia + ITE treatment, and meanwhile the cell viability increased significantly. Hypoxia could promote expression of TGF‐β1 protein rather than BMP2 and BMP9, and regulate phosphorylation levels of Samd2/3, ERK and p38 MAPK in different manners. In conclusion, ITE can promote the hypoxia‐induced transdifferentiation of HPAECs into SM‐like cells via TGF‐β/Smads and MAPK/ERK pathways.