Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression

Abstract Hemorrhage and hemolysis with subsequent heme release are implicated in many pathologies. Endothelial cells (ECs) encounter large amount of free heme after hemolysis and are at risk of damage from exogenous heme. Here we show that hemorrhage aggravates endoplasmic reticulum (ER) stress in h...

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Autores principales:	Dávid Pethő, Zoltán Hendrik, Annamária Nagy, Lívia Beke, Andreas Patsalos, László Nagy, Szilárd Póliska, Gábor Méhes, Csaba Tóth, László Potor, John W. Eaton, Harry S. Jacob, György Balla, József Balla, Tamás Gáll
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bc71b043d333425e8f8bbfb10cf802ad
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spelling	oai:doaj.org-article:bc71b043d333425e8f8bbfb10cf802ad2021-12-02T16:51:14ZHeme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression10.1038/s41598-021-89713-32045-2322https://doaj.org/article/bc71b043d333425e8f8bbfb10cf802ad2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89713-3https://doaj.org/toc/2045-2322Abstract Hemorrhage and hemolysis with subsequent heme release are implicated in many pathologies. Endothelial cells (ECs) encounter large amount of free heme after hemolysis and are at risk of damage from exogenous heme. Here we show that hemorrhage aggravates endoplasmic reticulum (ER) stress in human carotid artery plaques compared to healthy controls or atheromas without hemorrhage as demonstrated by RNA sequencing and immunohistochemistry. In EC cultures, heme also induces ER stress. In contrast, if cultured ECs are pulsed with heme arginate, cells become resistant to heme-induced ER (HIER) stress that is associated with heme oxygenase-1 (HO-1) and ferritin induction. Knocking down HO-1, HO-2, biliverdin reductase, and ferritin show that HO-1 is the ultimate cytoprotectant in acute HIER stress. Carbon monoxide-releasing molecules (CORMs) but not bilirubin protects cultured ECs from HIER stress via HO-1 induction, at least in part. Knocking down HO-1 aggravates heme-induced cell death that cannot be counterbalanced with any known cell death inhibitors. We conclude that endothelium and perhaps other cell types can be protected from HIER stress by induction of HO-1, and heme-induced cell death occurs via HIER stress that is potentially involved in the pathogenesis of diverse pathologies with hemolysis and hemorrhage including atherosclerosis.Dávid PethőZoltán HendrikAnnamária NagyLívia BekeAndreas PatsalosLászló NagySzilárd PóliskaGábor MéhesCsaba TóthLászló PotorJohn W. EatonHarry S. JacobGyörgy BallaJózsef BallaTamás GállNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-23 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dávid Pethő Zoltán Hendrik Annamária Nagy Lívia Beke Andreas Patsalos László Nagy Szilárd Póliska Gábor Méhes Csaba Tóth László Potor John W. Eaton Harry S. Jacob György Balla József Balla Tamás Gáll Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression
description	Abstract Hemorrhage and hemolysis with subsequent heme release are implicated in many pathologies. Endothelial cells (ECs) encounter large amount of free heme after hemolysis and are at risk of damage from exogenous heme. Here we show that hemorrhage aggravates endoplasmic reticulum (ER) stress in human carotid artery plaques compared to healthy controls or atheromas without hemorrhage as demonstrated by RNA sequencing and immunohistochemistry. In EC cultures, heme also induces ER stress. In contrast, if cultured ECs are pulsed with heme arginate, cells become resistant to heme-induced ER (HIER) stress that is associated with heme oxygenase-1 (HO-1) and ferritin induction. Knocking down HO-1, HO-2, biliverdin reductase, and ferritin show that HO-1 is the ultimate cytoprotectant in acute HIER stress. Carbon monoxide-releasing molecules (CORMs) but not bilirubin protects cultured ECs from HIER stress via HO-1 induction, at least in part. Knocking down HO-1 aggravates heme-induced cell death that cannot be counterbalanced with any known cell death inhibitors. We conclude that endothelium and perhaps other cell types can be protected from HIER stress by induction of HO-1, and heme-induced cell death occurs via HIER stress that is potentially involved in the pathogenesis of diverse pathologies with hemolysis and hemorrhage including atherosclerosis.
format	article
author	Dávid Pethő Zoltán Hendrik Annamária Nagy Lívia Beke Andreas Patsalos László Nagy Szilárd Póliska Gábor Méhes Csaba Tóth László Potor John W. Eaton Harry S. Jacob György Balla József Balla Tamás Gáll
author_facet	Dávid Pethő Zoltán Hendrik Annamária Nagy Lívia Beke Andreas Patsalos László Nagy Szilárd Póliska Gábor Méhes Csaba Tóth László Potor John W. Eaton Harry S. Jacob György Balla József Balla Tamás Gáll
author_sort	Dávid Pethő
title	Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression
title_short	Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression
title_full	Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression
title_fullStr	Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression
title_full_unstemmed	Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression
title_sort	heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/bc71b043d333425e8f8bbfb10cf802ad
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Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression

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