CCL20 is increased in hypercholesterolemic subjects and is upregulated by LDL in vascular smooth muscle cells: Role of NF-?B
Por:
Calvayrac O., Rodríguez-Calvo R., Alonso J., Orbe J., Martín-Ventura J.L., Guadall A., Gentile M., Juan-Babot O., Egido J., Beloqui O., Paramo J.A., Rodríguez C., Martínez-González J.
Publicada:
1 ene 2011
Resumen:
Objective-: Our aim was to analyze the regulation of CC Chemokine ligand 20 (CCL20) by LDL in human vascular smooth muscle cells (VSMC). Methods and Results-: In asymptomatic subjects, circulating CCL20 levels were higher in patients with hypercholesterolemia (18.5±3.2 versus 9.1±1.3 pg/mL; P<0.01). LDL induced the expression of CCL20 in VSMC in a dose-and time-dependent manner. Increased levels of CCL20 secreted by LDL-treated VSMC significantly induced human lymphocyte migration, an effect reduced by CCL20 silencing. The upregulation of CCL20 by LDL was dependent on the activation of kinase signaling pathways and NF-?B. By site-directed mutagenesis, electrophoretic mobility shift assay, and chromatin immunoprecipitation, we identified a NF-?B site (-80/-71) in CCL20 promoter critical for LDL responsiveness. Lysophosphatidic acid mimicked the upregulation of CCL20 induced by LDL, and minimal oxidation of LDL increased the ability of LDL to induce CCL20 through a mechanism that involves lysophosphatidic acid receptors. CCL20 was overexpressed in atherosclerotic lesions from coronary artery patients, colocalizing with VSMC. CCL20 was detected in conditioned media from healthy human aorta and its levels were significantly higher in secretomes from carotid endarterectomy specimens. Conclusion-: This study identifies CCL20 in atherosclerotic lesions and recognizes this chemokine as a mediator highly sensitive to the inflammatory response elicited by LDL. © 2011 American Heart Association. All rights reserved.
Filiaciones:
Calvayrac O.:
Centro de Investigación Cardiovascular, Institut Català de Ciències Cardiovasculars, Instituto de Investigaciones Biomédicas Sant Pau, c/Antoni Maria Claret 167, 08025 Barcelona, Spain
Rodríguez-Calvo R.:
Centro de Investigación Cardiovascular, Institut Català de Ciències Cardiovasculars, Instituto de Investigaciones Biomédicas Sant Pau, c/Antoni Maria Claret 167, 08025 Barcelona, Spain
Alonso J.:
Centro de Investigación Cardiovascular, Institut Català de Ciències Cardiovasculars, Instituto de Investigaciones Biomédicas Sant Pau, c/Antoni Maria Claret 167, 08025 Barcelona, Spain
Orbe J.:
Laboratory of Atherothrombosis, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
Martín-Ventura J.L.:
Vascular Research Laboratory, Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
Guadall A.:
Centro de Investigación Cardiovascular, Institut Català de Ciències Cardiovasculars, Instituto de Investigaciones Biomédicas Sant Pau, c/Antoni Maria Claret 167, 08025 Barcelona, Spain
Gentile M.:
Centro de Investigación Cardiovascular, Institut Català de Ciències Cardiovasculars, Instituto de Investigaciones Biomédicas Sant Pau, c/Antoni Maria Claret 167, 08025 Barcelona, Spain
Juan-Babot O.:
Centro de Investigación Cardiovascular, Institut Català de Ciències Cardiovasculars, Instituto de Investigaciones Biomédicas Sant Pau, c/Antoni Maria Claret 167, 08025 Barcelona, Spain
Egido J.:
Vascular Research Laboratory, Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
Beloqui O.:
Department of Internal Medicine, School of Medicine, University of Navarra, Pamplona, Spain
Paramo J.A.:
Laboratory of Atherothrombosis, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
Rodríguez C.:
Centro de Investigación Cardiovascular, Institut Català de Ciències Cardiovasculars, Instituto de Investigaciones Biomédicas Sant Pau, c/Antoni Maria Claret 167, 08025 Barcelona, Spain
Martínez-González J.:
Centro de Investigación Cardiovascular, Institut Català de Ciències Cardiovasculars, Instituto de Investigaciones Biomédicas Sant Pau, c/Antoni Maria Claret 167, 08025 Barcelona, Spain
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