Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombosis and pregnancy morbidity (PM) obstetric events together with persistent high titers of circulating antiphospholipid antibodies (aPL). Several mechanisms that explain the development of thrombosis and PM in APS includ...

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Autores principales:	Carlos M. Rodríguez, Manuela Velásquez-Berrío, Carolina Rúa, Marta Viana, Vikki M. Abrahams, Angela P. Cadavid, Angela M. Alvarez
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	antiphospholipid antibodies antiphospholipid syndrome endothelial cell mitochondria mTOR autophagy Physiology QP1-981
Acceso en línea:	https://doaj.org/article/5cda4908e2864e92a72bbf752980992b
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spelling	oai:doaj.org-article:5cda4908e2864e92a72bbf752980992b2021-12-01T14:06:53ZAntiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy1664-042X10.3389/fphys.2021.706743https://doaj.org/article/5cda4908e2864e92a72bbf752980992b2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphys.2021.706743/fullhttps://doaj.org/toc/1664-042XAntiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombosis and pregnancy morbidity (PM) obstetric events together with persistent high titers of circulating antiphospholipid antibodies (aPL). Several mechanisms that explain the development of thrombosis and PM in APS include the association of aPL with alterations in the coagulation cascade and inflammatory events. Other mechanisms disturbing cellular homeostases, such as mitochondrial dysfunction, autophagy, and cell proliferation, have been described in other autoimmune diseases. Therefore, the objective of this study was to investigate the impact of aPL from different patient populations on endothelial cell mitochondrial function, activation of the mammalian target of rapamycin (mTOR) and autophagy pathways, and cellular growth. Using an in vitro model, human umbilical vein endothelial cells (HUVECs) were treated with polyclonal immunoglobulin G (IgG) purified from the serum of women with both PM and vascular thrombosis (PM/VT), with VT only (VT), or with PM and non-criteria aPL (seronegative-obstetric APS, SN-OAPS). We included IgG from women with PM without aPL (PM/aPL-) and healthy women with previous uncomplicated pregnancies (normal human serum, NHS) as control groups. Mitochondrial function, mTOR activation, autophagy, and cell proliferation were evaluated by Western blotting, flow cytometry, and functional assays. IgG from women with PM/VT increased HUVEC mitochondrial hyperpolarization and activation of the mTOR and autophagic pathways, while IgG from patients with VT induced endothelial autophagy and cell proliferation in the absence of elevated mTOR activity or mitochondrial dysfunction. IgG from the SN-OAPS patient group had no effect on any of these HUVEC responses. In conclusion, aPL from women with PM and vascular events induce cellular stress evidenced by mitochondrial hyperpolarization and increased activation of the mTOR and autophagic pathways which may play a role in the pathogenesis of obstetric APS.Carlos M. RodríguezManuela Velásquez-BerríoCarolina RúaMarta VianaMarta VianaVikki M. AbrahamsAngela P. CadavidAngela P. CadavidAngela M. AlvarezFrontiers Media S.A.articleantiphospholipid antibodiesantiphospholipid syndromeendothelial cellmitochondriamTORautophagyPhysiologyQP1-981ENFrontiers in Physiology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	antiphospholipid antibodies antiphospholipid syndrome endothelial cell mitochondria mTOR autophagy Physiology QP1-981
spellingShingle	antiphospholipid antibodies antiphospholipid syndrome endothelial cell mitochondria mTOR autophagy Physiology QP1-981 Carlos M. Rodríguez Manuela Velásquez-Berrío Carolina Rúa Marta Viana Marta Viana Vikki M. Abrahams Angela P. Cadavid Angela P. Cadavid Angela M. Alvarez Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy
description	Antiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombosis and pregnancy morbidity (PM) obstetric events together with persistent high titers of circulating antiphospholipid antibodies (aPL). Several mechanisms that explain the development of thrombosis and PM in APS include the association of aPL with alterations in the coagulation cascade and inflammatory events. Other mechanisms disturbing cellular homeostases, such as mitochondrial dysfunction, autophagy, and cell proliferation, have been described in other autoimmune diseases. Therefore, the objective of this study was to investigate the impact of aPL from different patient populations on endothelial cell mitochondrial function, activation of the mammalian target of rapamycin (mTOR) and autophagy pathways, and cellular growth. Using an in vitro model, human umbilical vein endothelial cells (HUVECs) were treated with polyclonal immunoglobulin G (IgG) purified from the serum of women with both PM and vascular thrombosis (PM/VT), with VT only (VT), or with PM and non-criteria aPL (seronegative-obstetric APS, SN-OAPS). We included IgG from women with PM without aPL (PM/aPL-) and healthy women with previous uncomplicated pregnancies (normal human serum, NHS) as control groups. Mitochondrial function, mTOR activation, autophagy, and cell proliferation were evaluated by Western blotting, flow cytometry, and functional assays. IgG from women with PM/VT increased HUVEC mitochondrial hyperpolarization and activation of the mTOR and autophagic pathways, while IgG from patients with VT induced endothelial autophagy and cell proliferation in the absence of elevated mTOR activity or mitochondrial dysfunction. IgG from the SN-OAPS patient group had no effect on any of these HUVEC responses. In conclusion, aPL from women with PM and vascular events induce cellular stress evidenced by mitochondrial hyperpolarization and increased activation of the mTOR and autophagic pathways which may play a role in the pathogenesis of obstetric APS.
format	article
author	Carlos M. Rodríguez Manuela Velásquez-Berrío Carolina Rúa Marta Viana Marta Viana Vikki M. Abrahams Angela P. Cadavid Angela P. Cadavid Angela M. Alvarez
author_facet	Carlos M. Rodríguez Manuela Velásquez-Berrío Carolina Rúa Marta Viana Marta Viana Vikki M. Abrahams Angela P. Cadavid Angela P. Cadavid Angela M. Alvarez
author_sort	Carlos M. Rodríguez
title	Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy
title_short	Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy
title_full	Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy
title_fullStr	Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy
title_full_unstemmed	Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy
title_sort	antiphospholipid antibodies from women with pregnancy morbidity and vascular thrombosis induce endothelial mitochondrial dysfunction, mtor activation, and autophagy
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/5cda4908e2864e92a72bbf752980992b
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Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy

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