Increased CD74 expression in human atherosclerotic plaques: contribution to inflammatory responses in vascular cells

• Published in: Cardiovascular research 2009-08, Vol.83 (3), p.586-594
• Main Authors: Martín-Ventura, José Luis, Madrigal-Matute, Julio, Muñoz-Garcia, Begoña, Blanco-Colio, Luis Miguel, Van Oostrom, Melany, Zalba, Guillermo, Fortuño, Ana, Gomez-Guerrero, Carmen, Ortega, Luis, Ortiz, Alberto, Diez, Javier, Egido, Jesús
• Format: Article
• Language: English
• Subjects: Antigens, Differentiation, B-Lymphocyte - blood; Antigens, Differentiation, B-Lymphocyte - genetics; Antigens, Differentiation, B-Lymphocyte - metabolism; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Biomarkers; Biomarkers - metabolism; Blood and lymphatic vessels; Cardiology. Vascular system; Carotid Arteries - immunology; Carotid Arteries - pathology; Carotid Arteries - surgery; Carotid stenosis; Carotid Stenosis - immunology; Carotid Stenosis - pathology; Carotid Stenosis - surgery; Case-Control Studies; Cells, Cultured; Chemokine CCL2 - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endarterectomy, Carotid; Fibrosis; Histocompatibility Antigens Class II - blood; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - metabolism; Humans; Inflammation; Inflammation - immunology; Inflammation - pathology; Inflammation Mediators - blood; Inflammation Mediators - metabolism; Interferon-gamma - metabolism; Leukocytes, Mononuclear - immunology; Macrophages - immunology; Medical sciences; Muscle, Smooth, Vascular - immunology; Muscle, Smooth, Vascular - pathology; Muscle, Smooth, Vascular - surgery; Myocytes, Smooth Muscle - immunology; Myocytes, Smooth Muscle - pathology; Neurology; NF-kappa B - metabolism; Recombinant Proteins - metabolism; RNA Interference; Severity of Illness Index; Time Factors; Transfection; Tumor Necrosis Factor-alpha - metabolism; Tunica Intima - immunology; Tunica Media - immunology; Up-Regulation; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvp141

Aims The purpose of this study was to analyse the expression of CD74 in human atherosclerotic plaques and peripheral blood mononuclear cells (PBMC) as well as its potential participation in proinflammatory responses in cultured human vascular smooth muscle cells (VSMC). Methods and results CD74 expression was analysed in human atherosclerotic plaques (immunohistochemistry), PBMC (real-time PCR), and human aortic VSMC (real-time PCR and western blotting). Nuclear factor-κB (NF-κB) activation was assessed by southwestern histochemistry and electrophoretic mobility shift assay. Monocyte chemoattractant protein-1 (MCP-1) levels were studied by both real-time PCR and enzyme-linked immunosorbent assay. CD74 immunostaining was increased in the inflammatory vs. the fibrous region of atherosclerotic plaques (n = 70, 18.2 ± 1.3 vs. 7.8 ± 0.6% positive staining/mm2, P < 0.001). CD74 colocalized with the transcription factor NF-κB in both VSMC and macrophages. In cultured VSMC, CD74 expression was induced by interferon γ (IFNγ). Incubation with an agonistic anti-CD74 antibody or with IFNγ elicited MCP-1 expression, which was prevented by AKT and γ-secretase inhibitors. Moreover, CD74 small-interfering RNA decreased NF-κB activation and MCP-1 production induced by IFNγ in VSMC. Finally, CD74 mRNA levels in PBMC from patients with carotid stenosis were higher than in healthy subjects (n = 20, 3 ± 0.5 vs. 2 ± 0.5 AU, P < 0.001). Additionally, a linear trend between CD74 mRNA expression tertiles and intima-media thickness (IMT) was observed in PBMC from asymptomatic subjects (n = 185, P < 0.001). Conclusion CD74 levels are increased in plaques and PBMC from patients with carotid stenosis and are associated with IMT in subjects free from clinical cardiovascular diseases. CD74 could be a novel therapeutic target to decrease the inflammatory response in atherosclerosis.