Branched-chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation
Entity
UAM. Departamento de Farmacología; UAM. Departamento de Medicina; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)Publisher
John Wiley & Sons Ltd and Foundation for Cellular and Molecular MedicineDate
2018-10-01Citation
10.1111/jcmm.13759
Journal of Cellular and Molecular Medicine 22.10 (2018): 4948–4962
ISSN
1582-1838DOI
10.1111/jcmm.13759Funded by
This study was supported by Ministerio de Economía y Competitividad (MINECO SAF2016‐80305‐P), Instituto de Salud Carlos III (ISCIII) Fondo Europeo de Desarrollo Regional (FEDER) a way to build Europe (PI14/00386, PI14/0041, PIE13/00051, PI13/01488; PI17‐01495, CiberCV, CiberDEM), FP7 grant e‐PREDICE, by the Fundación Renal Iñigo Álvarez de Toledo (FRIAT)/Instituto Reina Sofía de Investigación Nefrológica and from Roche‐IdiPazProject
Gobierno de España. SAF2016‐80305‐P; Gobierno de España. PI14/00386; Gobierno de España. PI14/0041; Gobierno de España. PIE13/00051; Gobierno de España. PI13/01488; Gobierno de España. PI17‐01495; info:eu-repo/grantAgreement/EC/FP7/279074Editor's Version
https://doi.org/10.1111/jcmm.13759Subjects
Aorta; BCAA; Endothelial cells; Endothelial dysfunction; Inflammation; Oxidative stress; MedicinaRights
© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.Abstract
Branched‐chain amino acids (BCAA: leucine, isoleucine and valine) are essential amino acids implicated in glucose metabolism and maintenance of correct brain function. Elevated BCAA levels can promote an inflammatory response in peripheral blood mononuclear cells. However, there are no studies analysing the direct effects of BCAA on endothelial cells (ECs) and its possible modulation of vascular function. In vitro and ex vivo studies were performed in human ECs and aorta from male C57BL/6J mice, respectively. In ECs, BCAA (6 mmol/L) increased eNOS expression, reactive oxygen species production by mitochondria and NADPH oxidases, peroxynitrite formation and nitrotyrosine expression. Moreover, BCAA induced pro‐inflammatory responses through the transcription factor NF‐κB that resulted in the release of intracellular adhesion molecule‐1 and E‐selectin conferring endothelial activation and adhesion capacity to inflammatory cells. Pharmacological inhibition of mTORC1 intracellular signalling pathway decreased BCAA-induced pro‐oxidant and pro‐inflammatory effects in ECs. In isolated murine aorta, BCAA elicited vasoconstrictor responses, particularly in pre‐contracted vessels and after NO synthase blockade, and triggered endothelial dysfunction, effects that were inhibited by different antioxidants, further demonstrating the potential of BCAA to induce oxidative stress with functional impact. In summary, we demonstrate that elevated BCAA levels generate inflammation and oxidative stress in ECs, thereby facilitating inflammatory cells adhesion and endothelial dysfunction. This might contribute to the increased cardiovascular risk observed in patients with elevated BCAA blood levels.
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Google Scholar:Zhenyukh, Olha
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González-Amor, Maria
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Rodrigues Díez, Raúl
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Esteban, Vanesa
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Ruiz Ortega, Marta
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Salaices Sánchez, Mercedes
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Mas, Sebastian
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Briones Alonso, Ana María
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Egido, Jesus
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