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Endothelin-1 Induce...
Endothelin-1 Induces Endoplasmic Reticulum Stress by Activating the PLC-IP3 Pathway Implications for Placental Pathophysiology in Preeclampsia
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Jain, Arjun (författare)
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- Olovsson, Matts (författare)
- Uppsala universitet,Obstetrik & gynekologi
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Burton, Graham J. (författare)
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Yung, Hong-wa (författare)
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(creator_code:org_t)
- Elsevier BV, 2012
- 2012
- Engelska.
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 180:6, s. 2309-2320
- Relaterad länk:
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http://ajp.amjpathol...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
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- Recent evidence implicates placental endoplasmic reticulum (ER) stress in the pathophysiological characteristics of preeclampsia. Herein, we investigate whether endothelin (ET)-1, which induces Ca2+ release from the ER, can induce placental ER stress. Loss of ER Ca2+ 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)gamma 1 levels. By using inhibitors of PLC activation, U73122, and the inositol 1,4,5-triphosphate (IP3) receptor, xestospongin-C, we demonstrated that ET-1 induces ER stress via the PLC-IP3 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-IP3 pathway, with the potential for autocrine stimulation.
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