CCL20 Is Increased in Hypercholesterolemic Subjects and Is Upregulated By LDL in Vascular Smooth Muscle Cells: Role of NF-κB

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 31; no. 11; pp. 2733 - 2741
• Main Authors: Calvayrac, Olivier, Rodríguez-Calvo, Ricardo, Alonso, Judith, Orbe, Josune, Martín-Ventura, Jose Luis, Guadall, Anna, Gentile, Maurizio, Juan-Babot, Oriol, Egido, Jesus, Beloqui, Oscar, Paramo, José A., Rodríguez, Cristina, Martínez-González, José
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.11.2011; Lippincott Williams & Wilkins
• Subjects: Adult; Aged; Aorta - metabolism; Aorta - pathology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cells, Cultured; Chemokine CCL20 - metabolism; Coronary Artery Disease - metabolism; Coronary Artery Disease - pathology; Coronary Artery Disease - surgery; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dose-Response Relationship, Drug; Endarterectomy; Female; Fundamental and applied biological sciences. Psychology; Humans; Hypercholesterolemia - metabolism; Lipoproteins, LDL - pharmacology; Male; Medical sciences; Middle Aged; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; NF-kappa B - metabolism; Signal Transduction; Time Factors; Up-Regulation - drug effects; Up-Regulation - physiology; Vertebrates: cardiovascular system; Human; Metabolic diseases; Lipids; Smooth muscle; Cardiovascular disease; Hyperlipoproteinemia; vascular biology; Gene expression; Cholesterol; Vascular disease; Lipoprotein LDL; Hypercholesterolemia; Atherosclerosis; Dyslipemia; Molecular biology; lipoproteins
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.111.235721

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-κB. By site-directed mutagenesis, electrophoretic mobility shift assay, and chromatin immunoprecipitation, we identified a NF-κB 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.