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Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease
Tsilingiri, K. (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
de la Fuente, Hortensia (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Relaño, M. (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Sánchez-Díaz, R. (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Rodríguez, C. (Institut d'Investigació Biomèdica Sant Pau)
Crespo Asensio, Javier (Institut d'Investigació Biomèdica Sant Pau)
Sánchez-Cabo, F. (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Dopazo, A. (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Alonso-Lebrero, J. L. (Hospital Universitario de la Princesa (Madrid))
Vara, Alicia (Hospital Universitario de la Princesa (Madrid))
Vázquez, Jesús (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Casasnovas, José M (Centro Nacional de Biotecnología)
Alfonso, Fernando (Instituto de Investigación Hospital Universitario de la Princesa)
Ibanez, Borja (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Fuster, Valentín (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Martínez-González, J. (Institut d'Investigació Biomèdica Sant Pau)
Martín, P. (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Sánchez-Madrid, F. (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Universitat Autònoma de Barcelona

Data: 2019
Resum: Background: Although the role of Th17 and regulatory T cells in the progression of atherosclerosis has been highlighted in recent years, their molecular mediators remain elusive. We aimed to evaluate the association between the CD69 receptor, a regulator of Th17/regulatory T cell immunity, and atherosclerosis development in animal models and in patients with subclinical disease. Methods: Low-density lipoprotein receptor-deficient chimeric mice expressing or not expressing CD69 on either myeloid or lymphoid cells were subjected to a high fat diet. In vitro functional assays with human T cells were performed to decipher the mechanism of the observed phenotypes. Expression of CD69 and NR4A nuclear receptors was evaluated by reverse transcription-polymerase chain reaction in 305 male participants of the PESA study (Progression of Early Subclinical Atherosclerosis) with extensive (n=128) or focal (n=55) subclinical atherosclerosis and without disease (n=122). Results: After a high fat diet, mice lacking CD69 on lymphoid cells developed large atheroma plaque along with an increased Th17/regulatory T cell ratio in blood. Oxidized low-density lipoprotein was shown to bind specifically and functionally to CD69 on human T lymphocytes, inhibiting the development of Th17 cells through the activation of NR4A nuclear receptors. Participants of the PESA study with evidence of subclinical atherosclerosis displayed a significant CD69 and NR4A1 mRNA downregulation in peripheral blood leukocytes compared with participants without disease. The expression of CD69 remained associated with the risk of subclinical atherosclerosis in an adjusted multivariable logistic regression model (odds ratio, 0. 62; 95% CI, 0. 40-0. 94; P=0. 006) after adjustment for traditional risk factors, the expression of NR4A1, the level of oxidized low-density lipoprotein, and the counts of different leucocyte subsets. Conclusions: CD69 depletion from the lymphoid compartment promotes a Th17/regulatory T cell imbalance and exacerbates the development of atherosclerosis. CD69 binding to oxidized low-density lipoprotein on T cells induces the expression of anti-inflammatory transcription factors. Data from a cohort of the PESA study with subclinical atherosclerosis indicate that CD69 expression in PBLs inversely correlates with the presence of disease. The expression of CD69 remained an independent predictor of subclinical atherosclerosis after adjustment for traditional risk factors.
Ajuts: Ministerio de Economía y Competitividad SAF2017-82886-R
Ministerio de Economía y Competitividad SAF2015-64767-R
Instituto de Salud Carlos III PI16-01956
Ministerio de Economía y Competitividad BES-2015-072625
Nota: Altres ajuts: Funding was provided by European Research Council, ERC-2011-AdG294340-GENTRIS to Dr Sánchez-Madrid; Proyecto Integrado de Excelencia PIE13/041 and Fundació La Marató TV3 (20152330 31); and Comunidad Autónoma de Madrid CAM (S2017/BMD-3671) to Drs Martin and Sánchez-Madrid. Dr Tsilingiri is cofunded by the European Union Marie Curie Program. This research has been cofinanced by Fondo Europeo de Desarrollo Regional. Centro Nacional de Investigaciones Cardio-vasculares (CNIC), Madrid, Spain, is supported by the Ministerio de Ciencia, In-novación y Universidades, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). The PESA study is cofunded equally by the Pro CNIC Foundation and Banco Santander, Madrid, Spain.
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades. Creative Commons
Llengua: Anglès
Document: Article ; recerca ; Versió publicada
Matèria: Atherosclerosis ; CD69 antigen oxidized ; Low density lipoprotein ; Regulatory T lymphocytes ; Th17 cells
Publicat a: Circulation, Vol. 139 Núm. 2 (august 2019) , p. 243-255, ISSN 1524-4539

DOI: 10.1161/CIRCULATIONAHA.118.034326
PMID: 30586697


13 p, 1.9 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut de Recerca Sant Pau
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 Registre creat el 2020-06-03, darrera modificació el 2023-11-30



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