Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease
Por:
Tsilingiri, K, de la Fuente, H, Relano, M, Sanchez-Diaz, R, Rodriguez, C, Crespo, J, Sanchez-Cabo, F, Dopazo, A, Alonso-Lebrero, JL, Vara, A, Vazquez, J, Casasnovas, JM, Alfonso, F, Ibanez, B, Fuster, V, Martinez-Gonzalez, J, Martin, P, Sanchez-Madrid, F
Publicada:
8 ene 2019
Resumen:
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.
Filiaciones:
Tsilingiri, K:
Ctr Nacl Invest Cardiovasc Carlos III, Vasc Pathophysiol Area, Madrid, Spain
de la Fuente, H:
Inst Invest Sanitaria Hosp la Princesa, IIS IP, Dept Immunol, Madrid, Spain
CIBER Enfermedades Cardiovasc, Madrid, Spain
Relano, M:
Ctr Nacl Invest Cardiovasc Carlos III, Vasc Pathophysiol Area, Madrid, Spain
Sanchez-Diaz, R:
Ctr Nacl Invest Cardiovasc Carlos III, Vasc Pathophysiol Area, Madrid, Spain
CIBER Enfermedades Cardiovasc, Madrid, Spain
Rodriguez, C:
Hosp Santa Creu & Sant Pau, IIB St Pau, Inst Recerca, Programa ICCC, Barcelona, Spain
CIBER Enfermedades Cardiovasc, Madrid, Spain
Crespo, J:
Hosp Santa Creu & Sant Pau, IIB St Pau, Inst Recerca, Programa ICCC, Barcelona, Spain
Sanchez-Cabo, F:
Ctr Nacl Invest Cardiovasc Carlos III, Bioinformat Unit, Madrid, Spain
Dopazo, A:
Ctr Nacl Invest Cardiovasc Carlos III, Genom Unit, Madrid, Spain
Alonso-Lebrero, JL:
Inst Invest Sanitaria Hosp la Princesa, IIS IP, Dept Immunol, Madrid, Spain
Vara, A:
Inst Invest Sanitaria Hosp la Princesa, IIS IP, Dept Immunol, Madrid, Spain
Vazquez, J:
Ctr Nacl Invest Cardiovasc Carlos III, Prote Unit, Madrid, Spain
CIBER Enfermedades Cardiovasc, Madrid, Spain
Casasnovas, JM:
Ctr Nacl Biotecnol, Madrid, Spain
Alfonso, F:
Inst Invest Sanitaria Hosp la Princesa, IIS IP, Dept Cardiol, Madrid, Spain
Ibanez, B:
Ctr Nacl Invest Cardiovasc Carlos III, Myocardial Pathophysiol Area, Madrid, Spain
IIS Fdn Jimenez Diaz Univ Hosp, Madrid, Spain
CIBER Enfermedades Cardiovasc, Madrid, Spain
Fuster, V:
Ctr Nacl Invest Cardiovasc Carlos III, Vasc Pathophysiol Area, Madrid, Spain
Icahn Sch Med Mt Sinai, Cardiovasc Inst, New York, NY 10029 USA
Martinez-Gonzalez, J:
Inst Invest Biomed Barcelona, IIB St Pau, Barcelona, Spain
CIBER Enfermedades Cardiovasc, Madrid, Spain
Martin, P:
Ctr Nacl Invest Cardiovasc Carlos III, Vasc Pathophysiol Area, Madrid, Spain
CIBER Enfermedades Cardiovasc, Madrid, Spain
Sanchez-Madrid, F:
Ctr Nacl Invest Cardiovasc Carlos III, Vasc Pathophysiol Area, Madrid, Spain
Inst Invest Sanitaria Hosp la Princesa, IIS IP, Dept Immunol, Madrid, Spain
CIBER Enfermedades Cardiovasc, Madrid, Spain
Green Published, Hybrid Gold
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