Regulation and role of endoglin in cholesterol-induced endothelial and vascular dysfunction in vivo and in vitro
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
30753095
DOI
10.1096/fj.201802245r
Knihovny.cz E-resources
- Keywords
- endothelial cells, hypercholesterolemia, mice, oxysterols,
- MeSH
- Aorta cytology metabolism pathology MeSH
- Apolipoproteins E genetics MeSH
- Plaque, Atherosclerotic etiology genetics metabolism MeSH
- beta-Cyclodextrins pharmacology MeSH
- Endothelium, Vascular drug effects metabolism pathology MeSH
- Cholesterol metabolism MeSH
- Endoglin genetics metabolism MeSH
- Hypercholesterolemia complications genetics metabolism MeSH
- Indazoles pharmacology MeSH
- Kruppel-Like Factor 6 metabolism MeSH
- Cells, Cultured MeSH
- Isonicotinic Acids pharmacology MeSH
- Receptors, LDL genetics MeSH
- Humans MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- NF-kappa B metabolism MeSH
- Nitric Oxide metabolism MeSH
- P-Selectin metabolism MeSH
- Smad Proteins metabolism MeSH
- Nitric Oxide Synthase Type III metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Apolipoproteins E MeSH
- beta-Cyclodextrins MeSH
- Cholesterol MeSH
- Endoglin MeSH
- Indazoles MeSH
- Klf6 protein, mouse MeSH Browser
- Kruppel-Like Factor 6 MeSH
- Isonicotinic Acids MeSH
- Receptors, LDL MeSH
- NF-kappa B MeSH
- Nitric Oxide MeSH
- P-Selectin MeSH
- PHA 408 MeSH Browser
- Smad Proteins MeSH
- Nitric Oxide Synthase Type III MeSH
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-κB in HAECs. 7K-induced Eng expression was prevented by the treatment with 2-hydroxypropyl-β-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.-Vicen, M., Vitverova, B., Havelek, R., Blazickova, K., Machacek, M., Rathouska, J., Najmanová, I., Dolezelova, E., Prasnicka, A., Sternak, M., Bernabeu, C., Nachtigal, P. Regulation and role of endoglin in cholesterol-induced endothelial and vascular dysfunction in vivo and in vitro.
Biomedical Research Networking Center on Rare Diseases Madrid Spain
Center for Biological Research Spanish National Research Council Madrid Spain
Jagiellonian Centre for Experimental Therapeutics Bobrzynskiego Krakow Poland
References provided by Crossref.org
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