Dysregulated Autophagy Leads to Oxidative Stress and Aberrant Expression of ABC Transporters in Women with Early Miscarriage

Early miscarriage (EMC) is a devastating obstetrical complication. ATP-binding cassette (ABC) transporters mediate cholesterol transfer across the placenta and enhance cell survival by effluxing substrates from target cells in the presence of stressors. Recent evidence reports an intricate interplay...

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Autores principales:	Saira Shahnawaz, Usman Shah Nawaz, Jonas Zaugg, Ghulam Hussain, Nadia Malik, Muhammad Zahoor-ul-Hassan Dogar, Shoaib Ahmad Malik, Christiane Albrecht
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	ATP-binding cassette (ABC) transporters autophagy antioxidant early miscarriage oxidative stress placenta Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/a06336cc3d274ffdb226d21d3600e4a9
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spelling	oai:doaj.org-article:a06336cc3d274ffdb226d21d3600e4a92021-11-25T16:27:38ZDysregulated Autophagy Leads to Oxidative Stress and Aberrant Expression of ABC Transporters in Women with Early Miscarriage10.3390/antiox101117422076-3921https://doaj.org/article/a06336cc3d274ffdb226d21d3600e4a92021-10-01T00:00:00Zhttps://www.mdpi.com/2076-3921/10/11/1742https://doaj.org/toc/2076-3921Early miscarriage (EMC) is a devastating obstetrical complication. ATP-binding cassette (ABC) transporters mediate cholesterol transfer across the placenta and enhance cell survival by effluxing substrates from target cells in the presence of stressors. Recent evidence reports an intricate interplay between autophagy and ABC transporters. We hypothesized that dysregulated autophagy and oxidative stress (OS) in the placenta leads to abnormal expression of membrane transporters contributing to poor pregnancy survival in EMC. We determined mRNA and protein expression of autophagy genes (Beclin-1/Bcl-2/LC3I/LC3II/p62) and ABC transporters (ABCA1/ABCG1/ABCG2) in placentae from EMC patients (<i>n</i> = 20), term controls (<i>n</i> = 19), first trimester (<i>n</i> = 6), and term controls (<i>n</i> = 5) controls. Oxidative/antioxidant status and biomarkers of oxidative damage were evaluated in maternal serum and placentae from EMC and healthy controls. In EMC, placental expression of LC3II/LC3I as well as of the key autophagy regulatory proteins Beclin-1 and Bcl-2 were reduced, whereas p62 was increased. Both in the serum and placentae of EMC patients, total OS was elevated reflected by increased oxidative damage markers (8-OHdG/malondialdehyde/carbonyl formation) accompanied by diminished levels of total antioxidant status, catalase, and total glutathione. Furthermore, we found reduced ABCG1 and increased ABCG2 expression. These findings suggest that a decreased autophagy status triggers Bcl-2-dependent OS leading to macromolecule damage in EMC placentae. The decreased expression of ABCG1 contributes to reduced cholesterol export to the growing fetus. Increasing ABCG2 expression could represent a protective feedback mechanism under inhibited autophagy conditions. In conclusion, dysregulated autophagy combined with increased oxidative toxicity and aberrant expression of placental ABC transporters affects materno-fetal health in EMC.Saira ShahnawazUsman Shah NawazJonas ZauggGhulam HussainNadia MalikMuhammad Zahoor-ul-Hassan DogarShoaib Ahmad MalikChristiane AlbrechtMDPI AGarticleATP-binding cassette (ABC) transportersautophagyantioxidantearly miscarriageoxidative stressplacentaTherapeutics. PharmacologyRM1-950ENAntioxidants, Vol 10, Iss 1742, p 1742 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ATP-binding cassette (ABC) transporters autophagy antioxidant early miscarriage oxidative stress placenta Therapeutics. Pharmacology RM1-950
spellingShingle	ATP-binding cassette (ABC) transporters autophagy antioxidant early miscarriage oxidative stress placenta Therapeutics. Pharmacology RM1-950 Saira Shahnawaz Usman Shah Nawaz Jonas Zaugg Ghulam Hussain Nadia Malik Muhammad Zahoor-ul-Hassan Dogar Shoaib Ahmad Malik Christiane Albrecht Dysregulated Autophagy Leads to Oxidative Stress and Aberrant Expression of ABC Transporters in Women with Early Miscarriage
description	Early miscarriage (EMC) is a devastating obstetrical complication. ATP-binding cassette (ABC) transporters mediate cholesterol transfer across the placenta and enhance cell survival by effluxing substrates from target cells in the presence of stressors. Recent evidence reports an intricate interplay between autophagy and ABC transporters. We hypothesized that dysregulated autophagy and oxidative stress (OS) in the placenta leads to abnormal expression of membrane transporters contributing to poor pregnancy survival in EMC. We determined mRNA and protein expression of autophagy genes (Beclin-1/Bcl-2/LC3I/LC3II/p62) and ABC transporters (ABCA1/ABCG1/ABCG2) in placentae from EMC patients (<i>n</i> = 20), term controls (<i>n</i> = 19), first trimester (<i>n</i> = 6), and term controls (<i>n</i> = 5) controls. Oxidative/antioxidant status and biomarkers of oxidative damage were evaluated in maternal serum and placentae from EMC and healthy controls. In EMC, placental expression of LC3II/LC3I as well as of the key autophagy regulatory proteins Beclin-1 and Bcl-2 were reduced, whereas p62 was increased. Both in the serum and placentae of EMC patients, total OS was elevated reflected by increased oxidative damage markers (8-OHdG/malondialdehyde/carbonyl formation) accompanied by diminished levels of total antioxidant status, catalase, and total glutathione. Furthermore, we found reduced ABCG1 and increased ABCG2 expression. These findings suggest that a decreased autophagy status triggers Bcl-2-dependent OS leading to macromolecule damage in EMC placentae. The decreased expression of ABCG1 contributes to reduced cholesterol export to the growing fetus. Increasing ABCG2 expression could represent a protective feedback mechanism under inhibited autophagy conditions. In conclusion, dysregulated autophagy combined with increased oxidative toxicity and aberrant expression of placental ABC transporters affects materno-fetal health in EMC.
format	article
author	Saira Shahnawaz Usman Shah Nawaz Jonas Zaugg Ghulam Hussain Nadia Malik Muhammad Zahoor-ul-Hassan Dogar Shoaib Ahmad Malik Christiane Albrecht
author_facet	Saira Shahnawaz Usman Shah Nawaz Jonas Zaugg Ghulam Hussain Nadia Malik Muhammad Zahoor-ul-Hassan Dogar Shoaib Ahmad Malik Christiane Albrecht
author_sort	Saira Shahnawaz
title	Dysregulated Autophagy Leads to Oxidative Stress and Aberrant Expression of ABC Transporters in Women with Early Miscarriage
title_short	Dysregulated Autophagy Leads to Oxidative Stress and Aberrant Expression of ABC Transporters in Women with Early Miscarriage
title_full	Dysregulated Autophagy Leads to Oxidative Stress and Aberrant Expression of ABC Transporters in Women with Early Miscarriage
title_fullStr	Dysregulated Autophagy Leads to Oxidative Stress and Aberrant Expression of ABC Transporters in Women with Early Miscarriage
title_full_unstemmed	Dysregulated Autophagy Leads to Oxidative Stress and Aberrant Expression of ABC Transporters in Women with Early Miscarriage
title_sort	dysregulated autophagy leads to oxidative stress and aberrant expression of abc transporters in women with early miscarriage
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a06336cc3d274ffdb226d21d3600e4a9
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Dysregulated Autophagy Leads to Oxidative Stress and Aberrant Expression of ABC Transporters in Women with Early Miscarriage

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