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N-acetylcysteine, xCT and suppression of Maxi-chloride channel activity in human placenta

Lofthouse, Emma M. and Manousopoulou, Antigoni and Cleal, Jane K. and O'Kelly, Ita M. and Poore, Kirsten R. and Garbis, Spiros D. and Lewis, Rohan M. (2021) N-acetylcysteine, xCT and suppression of Maxi-chloride channel activity in human placenta. Placenta, 110 . pp. 46-55. ISSN 0143-4004. doi:10.1016/j.placenta.2021.05.009. https://resolver.caltech.edu/CaltechAUTHORS:20210629-202447658

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Abstract

Introduction: Placental oxidative stress features in pregnancy pathologies but in clinical trials antioxidant supplementation has not improved outcomes. N-acetylcysteine (NAC) stimulates glutathione production and is proposed as a therapeutic agent in pregnancy. However, key elements of N-acetylcysteine biology, including its cellular uptake mechanism, remains unclear. This study explores how the cystine/glutamate transporter xCT may mediate N-acetylcysteine uptake and how N-acetylcysteine alters placental redox status. Methods: The involvement of xCT in NAC uptake by the human placenta was studied in perfused placenta and Xenopus oocytes. The effect of short-term N-acetylcysteine exposure on the placental villous proteome was determined using LC-MS. The effect of N-acetylcysteine on Maxi-chloride channel activity was investigated in perfused placenta, villous fragments and cell culture. Results: Maternoplacental N-acetylcysteine administration stimulated intracellular glutamate efflux suggesting a role of the exchange transporter xCT, which was localised to the microvillous membrane of the placental syncytiotrophoblast. Placental exposure to a bolus of N-acetylcysteine inhibited subsequent activation of the redox sensitive Maxi-chloride channel independently of glutathione synthesis. Stable isotope quantitative proteomics of placental villi treated with N-acetylcysteine demonstrated changes in pathways associated with oxidative stress, apoptosis and the acute phase response. Discussion: This study suggests that xCT mediates N-acetylcysteine uptake into the placenta and that N-acetylcysteine treatment of placental tissue alters the placental proteome while regulating the redox sensitive Maxi-chloride channel. Interestingly N-acetylcysteine had antioxidant effects independent of the glutathione pathway. Effective placental antioxidant therapy in pregnancy may require maintaining the balance between normalising redox status without inhibiting physiological redox signalling.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.placenta.2021.05.009DOIArticle
ORCID:
AuthorORCID
Lofthouse, Emma M.0000-0002-0175-5590
Manousopoulou, Antigoni0000-0001-5028-1865
Cleal, Jane K.0000-0001-7978-4327
Garbis, Spiros D.0000-0002-1050-0805
Lewis, Rohan M.0000-0003-4044-9104
Additional Information:© 2021 Elsevier Ltd. Received 5 March 2021, Revised 4 May 2021, Accepted 26 May 2021, Available online 5 June 2021. We would like to thank The Gerald Kerkut Charitable Trust and the BBSRC (BB/L020823/1) for their funding and the midwives and patients at the Princess Anne Hospital, Southampton for their help in collecting placentas. Data availability statement: The data that support the findings of this study are openly available in ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD011425 (Reviewer account details: Username: reviewer25729@ebi.ac.uk Password: VIH27nwJ). The authors declare no conflict of interest.
Funders:
Funding AgencyGrant Number
Gerald Kerkut Charitable TrustUNSPECIFIED
Biotechnology and Biological Sciences Research Council (BBSRC)BB/L020823/1
Subject Keywords:Antioxidant; Redox; Membrane transport
DOI:10.1016/j.placenta.2021.05.009
Record Number:CaltechAUTHORS:20210629-202447658
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210629-202447658
Official Citation:Emma M. Lofthouse, Antigoni Manousopoulou, Jane K. Cleal, Ita M. O'Kelly, Kirsten R. Poore, Spiros D. Garbis, Rohan M. Lewis, N-acetylcysteine, xCT and suppression of Maxi-chloride channel activity in human placenta, Placenta, Volume 110, 2021, Pages 46-55, ISSN 0143-4004, https://doi.org/10.1016/j.placenta.2021.05.009. (https://www.sciencedirect.com/science/article/pii/S014340042100165X)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109654
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:29 Jun 2021 22:41
Last Modified:29 Jun 2021 22:41

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