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Am J Pathol. 2012 Jun;180(6):2309-20. doi: 10.1016/j.ajpath.2012.03.005. Epub 2012 Apr 12.

Endothelin-1 induces endoplasmic reticulum stress by activating the PLC-IP(3) pathway: implications for placental pathophysiology in preeclampsia.

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  • 1Center for Trophoblast Research, Department of Physiology Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.

Abstract

Recent evidence implicates placental endoplasmic reticulum (ER) stress in the pathophysiological characteristics of preeclampsia. Herein, we investigate whether endothelin (ET)-1, which induces Ca(2+) release from the ER, can induce placental ER stress. Loss of ER Ca(2+) homeostasis impairs post-translational modification of proteins, triggering ER stress-response pathways. IHC confirmed the presence of both ET-1 and its receptors in the syncytiotrophoblast. Protein levels and immunoreactivity of ET-1 and the endothelin B receptor (ETBR) were increased in preeclamptic samples compared with normotensive controls. JEG-3 and BeWo choriocarcinoma cells treated with ET-1 displayed an increase in ER stress markers. ET-1 induced phospho-activation of the ETBR. Treating cells with BQ788, an ETBR antagonist, or small-interfering RNA knockdown of the receptor inhibited induction of ER stress. ET-1 also stimulated p-phospholipase C (PLC)γ1 levels. By using inhibitors of PLC activation, U73122, and the inositol 1,4,5-triphosphate (IP(3)) receptor, xestospongin-C, we demonstrated that ET-1 induces ER stress via the PLC-IP(3) pathway. Furthermore, ET-1 levels increased in the syncytiotrophoblast of explants from normal placentas after hypoxia-reoxygenation in vitro. Conditioned medium from hypoxia-reoxygenation explants also contained higher ET-1 levels, which induced ER stress in JEG-3 cells that was abolished by an ET-1-neutralizing antibody. Collectively, the data show that ET-1 induced ER stress in trophoblasts via the ETBR and initiation of signaling through the PLC-IP(3) pathway, with the potential for autocrine stimulation.

Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

PMID:
22503784
[PubMed - indexed for MEDLINE]
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