Regulation and role of endoglin in cholesterol-induced endothelial and vascular dysfunction in vivo and in vitro

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F19%3A10400925" target="_blank" >RIV/00216208:11160/19:10400925 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11150/19:10400925

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=M14WFXnMhf" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=M14WFXnMhf</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1096/fj.201802245R" target="_blank" >10.1096/fj.201802245R</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Regulation and role of endoglin in cholesterol-induced endothelial and vascular dysfunction in vivo and in vitro

Popis výsledku v původním jazyce

Our objective was to investigate the effect of cholesterol [hypercholesterolemia and 7-ketocholesterol (7K)] on endoglin (Eng) expression and regulation with respect to endothelial or vascular dysfunction in vivo and in vitro. In vivo experiments were performed in 2-mo-old atherosclerosis-prone apolipoprotein E-deficient/LDL receptor-deficient (ApoE(-/-)/LDLR(-/-)) female mice and their wild-type C57BL/6J littermates. In in vitro experiments, human aortic endothelial cells (HAECs) were treated with 7K. ApoE(-/-)/LDLR(-/-) mice developed hypercholesterolemia accompanied by increased circulating levels of P-selectin and Eng and a disruption of NO metabolism. Functional analysis of the aorta demonstrated impaired vascular reactivity, and Western blot analysis revealed down-regulation of membrane Eng/Smad2/3/eNOS signaling in ApoE(-/-)/LDLR(-/-) mice. 7K increased Eng expression via Krüppel-like factor 6 (KLF6), liver X nuclear receptor, and NF-kappaB in HAECs. 7K-induced Eng expression was prevented by the treatment with 2-hydroxypropyl-beta-cyclodextrin; 8-{[5-chloro-2-(4-methylpiperazin-1-yl) pyridine-4-carbonyl] amino}-1-(4-fluorophenyl)-4,5-dihydrobenzo[g]indazole-3-carboxamide; or by KLF6 silencing. 7K induced increased adhesion and transmigration of monocytic human leukemia promonocytic cell line cells and was prevented by Eng silencing. We concluded that hypercholesterolemia altered Eng expression and signaling, followed by endothelial or vascular dysfunction before formation of atherosclerotic lesions in ApoE(-/-)/LDLR(-/-) mice. By contrast, 7K increased Eng expression and induced inflammation in HAECs, which was followed by an increased adhesion and transmigration of monocytes via endothelium, which was prevented by Eng inhibition. Thus, we propose a relevant role for Eng in endothelial or vascular dysfunction or inflammation when exposed to cholesterol.

Název v anglickém jazyce

Regulation and role of endoglin in cholesterol-induced endothelial and vascular dysfunction in vivo and in vitro

Popis výsledku anglicky

Our objective was to investigate the effect of cholesterol [hypercholesterolemia and 7-ketocholesterol (7K)] on endoglin (Eng) expression and regulation with respect to endothelial or vascular dysfunction in vivo and in vitro. In vivo experiments were performed in 2-mo-old atherosclerosis-prone apolipoprotein E-deficient/LDL receptor-deficient (ApoE(-/-)/LDLR(-/-)) female mice and their wild-type C57BL/6J littermates. In in vitro experiments, human aortic endothelial cells (HAECs) were treated with 7K. ApoE(-/-)/LDLR(-/-) mice developed hypercholesterolemia accompanied by increased circulating levels of P-selectin and Eng and a disruption of NO metabolism. Functional analysis of the aorta demonstrated impaired vascular reactivity, and Western blot analysis revealed down-regulation of membrane Eng/Smad2/3/eNOS signaling in ApoE(-/-)/LDLR(-/-) mice. 7K increased Eng expression via Krüppel-like factor 6 (KLF6), liver X nuclear receptor, and NF-kappaB in HAECs. 7K-induced Eng expression was prevented by the treatment with 2-hydroxypropyl-beta-cyclodextrin; 8-{[5-chloro-2-(4-methylpiperazin-1-yl) pyridine-4-carbonyl] amino}-1-(4-fluorophenyl)-4,5-dihydrobenzo[g]indazole-3-carboxamide; or by KLF6 silencing. 7K induced increased adhesion and transmigration of monocytic human leukemia promonocytic cell line cells and was prevented by Eng silencing. We concluded that hypercholesterolemia altered Eng expression and signaling, followed by endothelial or vascular dysfunction before formation of atherosclerotic lesions in ApoE(-/-)/LDLR(-/-) mice. By contrast, 7K increased Eng expression and induced inflammation in HAECs, which was followed by an increased adhesion and transmigration of monocytes via endothelium, which was prevented by Eng inhibition. Thus, we propose a relevant role for Eng in endothelial or vascular dysfunction or inflammation when exposed to cholesterol.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

The FASEB Journal

ISSN

0892-6638

e-ISSN

—

Svazek periodika

33

Číslo periodika v rámci svazku

5

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

16

Strana od-do

6099-6114

Kód UT WoS článku

000466932600025

EID výsledku v databázi Scopus

2-s2.0-85065469614