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Inhibition of Endoplasmic Reticulum Stress Apoptosis by Estrogen Protects Human Umbilical Vein Endothelial Cells Through the PI3 Kinase–Akt Signaling Pathway
Author(s) -
Su Qing,
Wang Yu,
Yang Xin,
Li XiaoDong,
Qi YongFen,
He XiaoJing,
Wang YanJie
Publication year - 2017
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.26120
Subject(s) - ly294002 , endoplasmic reticulum , signal transduction , p38 mitogen activated protein kinases , umbilical vein , atf6 , protein kinase a , unfolded protein response , kinase , microbiology and biotechnology , protein kinase b , downregulation and upregulation , estrogen receptor , apoptosis , pi3k/akt/mtor pathway , phosphoinositide 3 kinase , tunicamycin , biology , chemistry , biochemistry , in vitro , genetics , cancer , breast cancer , gene
We aimed to investigate whether the cardioprotective effect of estrogen is mediated by inhibiting the apoptosis induced by endoplasmic reticulum stress (ERS) and to explore the underlying signaling pathway responsible for this effect. The effect of estrogen on ERS apoptosis, the mechanism responsible for that effect, and the ERS signaling pathways were examined in human umbilical vein endothelial cells (HUVECs) and measured using Western blot, Hoechst stains and caspase‐3 activity assay. In vitro, 10 −8 mol/l estrogen directly inhibited the up‐regulation of the ERS marker glucose‐regulated protein 78 (GRP78) and ERS apoptosis marker C/EBP homologous protein (CHOP). ERS was induced using the ERS inducer tunicamycin (TM, 10 µmol/l) or dithiothreitol (DTT, 2 mmol/l) in HUVECs. Estrogen can also decrease the apoptosis cells mediated by ERS, based on the results of Hoechst stains. Protein expression in the three main ERS signaling pathways was upregulated in TM‐ or DTT‐induced HUVEC ERS. Increases in p‐PERK/PERK were the most obvious, and estrogen significantly inhibited the upregulation of p‐PERK/PERK, p‐IRE1/IRE1, and ATF6. These inhibitory effects were abolished by specific estrogen receptor antagonists (ICI182, 780, and G15) and inhibitors of the E 2 post‐receptor signaling pathway, including phosphoinositide 3‐kinase (PI3K) inhibitor LY294002, p38‐mitogen activated protein kinase (p38‐MAPK) inhibitor SB203580, c‐Jun N‐terminal kinase (JNK) inhibitor SP600125 and extracellular signal‐regulated kinases1/2 (ERK1/2) inhibitor U0126; of these inhibitors, LY294002 was the most effective. Further experiments showed that when the PI3K pathway was blocked, the inhibitory effect of estrogen on ERS apoptosis was reduced. Estrogen can prevent HUVEC apoptosis by inhibiting the ERS apoptosis triggered by the PERK pathway, which may protect vascular endothelial cells and the cardiovascular system. The main mechanism responsible for ERS inhibition is the activation of the PI3K‐Akt pathway for the activated estrogen receptor. J. Cell. Biochem. 118: 4568–4574, 2017. © 2017 Wiley Periodicals, Inc.