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Title

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

Other TitlesShort title: endoglin, cholesterol and endothelial dysfunction
AuthorsVicen, Matej; Vitverova, Barbora; Havelek, Radim; Blazickova, Katerina; Machacek, Miloslav; Rathouska, Jana; Najmanová, Iveta; Dolezelova, Eva; Prasnicka, Alena; Bernabéu, Carmelo ; Nachtigal, Petr
KeywordsEndoglin
Hypercholesterolemia
Oxysterols
Endothelial dysfunction
Mice
Issue Date12-Feb-2019
PublisherFederation of American Societies for Experimental Biology
CitationFASEB J fj201802245R (2019)
AbstractObjective: To investigate the effect of cholesterol (hypercholesterolemia/7- ketocholesterol) on endoglin expression and regulation with respect to endothelial/vascular dysfunction in vivo and in vitro.
Approach and results: In vivo experiments were performed in two-month-old ApoE-/-/LDLR-/- female mice and their wild type C57BL/6J littermates. In in vitro experiments, Human Aortic Endothelial Cells (HAECs) were treated with 7-ketocholesterol (7K). ApoE-/-/LDLR-/- mice developed hypercholesterolemia accompanied by increased circulating levels of P-selectin and endoglin and a disruption of NO metabolism. Functional analysis of aorta demonstrated impaired vascular reactivity and Western blot analysis revealed downregulation of membrane Eng/Smad2/3/eNOS signaling in ApoE-/-/LDLR-/- mice. 7K increased endoglin expression via KLF6, LXR and NF-κB in HAECs. 7K-induced endoglin expression was prevented by the treatment with 2-hydroxypropyl-β-cyclodextrin, PHA-408 or by KLF6 silencing. 7K induced increased adhesion and transmigration of monocytic THP-1 cells, was prevented by endoglin silencing.
Conclusions: Hypercholesterolemia altered endoglin expression and signaling, followed by endothelial/vascular dysfunction before formation of atherosclerotic lesions in ApoE-/-/LDLR- /- mice. By contrast, 7-ketocholesterol increased endoglin expression, and induced inflammation in HAECs, which was followed by an increased adhesion and transmigration of monocytes via endothelium, which was prevented by endoglin inhibition. Thus, we propose a relevant role for endoglin in endothelial/vascular dysfunction/inflammation when exposed to cholesterol
Description41 p.-7 fig.
Publisher version (URL)https://doi.org/10.1096/fj.201802245R
URIhttp://hdl.handle.net/10261/176682
DOIhttp://dx.doi.org/10.1096/fj.201802245R
ISSN0892-6638
E-ISSN1530-6860
Appears in Collections:(CIB) Artículos
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