Regulation and role of endoglin in cholesterol-induced endothelial and vascular dysfunction in vivo and in vitro
| Autor: | Vicen, Matej, Vitverova, Barbora, Havelek, Radim, Blazickova, Katerina, Machacek, Miloslav, Rathouska, Jana, Najmanová, Iveta, Dolezelova, Eva, Prasnicka, Alena, Bernabéu, Carmelo, Nachtigal, Petr |
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| Přispěvatelé: | Charles University (Czech Republic), Czech Health Research Council, Consejo Superior de Investigaciones Científicas (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Instituto de Salud Carlos III, European Commission, Vicen, Matej [0000-0002-7568-6989], Vitverova, Barbora [0000-0002-4446-2712], Havelek, Radim [0000-0003-0528-1334], Blazickova, Katerina [0000-0002-1654-0277], Rathouska, Jana [0000-0001-6363-9715], Najmanová, Iveta [0000-0002-8443-0512], Dolezelova, Eva [0000-0002-1397-6016], Prasnicka, Alena [0000-0002-6671-0318], Sternak, Magdalena[0000-0001-9690-5231], Bernabéu, Carmelo [0000-0002-1563-6162], Nachtigal, Petr [0000-0001-9568-7295] |
| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | 41 p.-7 fig. Objective: 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 This work was supported by project EFSA-CDN (No. CZ.02.1.01/0.0/0.0/16_019/0000841) cofunded by ERDF, grants of Charles University Grant Agency, GAUK 1158413C, 1216217,Specific University Research SVV/2017/260414 and Czech Health Research Council (AZV CR17-31754A). CB was supported by grants from Consejo Superior de Investigaciones Cientificas(201420E039) and Centro de Investigacion Biomedica en Red de Enfermedades Raras(CIBERER; ISCIII-CB06/07/0038). CIBERER is an initiative of the Instituto de Salud Carlos III(ISCIII) of Spain supported by FEDER funds. |
| Databáze: | OpenAIRE |
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