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Cardiovascular Research Advance Access first published online on May 7, 2009
This version [Corrected Proof] published online on June 4, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp141
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

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

José Luis Martín-Ventura1,*, Julio Madrigal-Matute1, Begoña Muñoz-Garcia1, Luis Miguel Blanco-Colio1, Melany Van Oostrom1, Guillermo Zalba2, Ana Fortuño2, Carmen Gomez-Guerrero1, Luis Ortega3, Alberto Ortiz1, Javier Diez2,4 and Jesús Egido1

1 Renal and Vascular Research Lab, Fundación Jimenez Diaz, Autonoma University, Madrid, Spain
2 Division of Cardiovascular Sciences, Center for Applied Medical Research University of Navarra, Pamplona, Spain
3 Anatomy Pathology Services, Hospital Clínico de San Carlos, Universidad Complutense, Madrid, Spain
4 Department of Cardiology and Cardiovascular Surgery, University Clinic, University of Navarra, Pamplona, Spain

* Corresponding author. E-mail address: jlmartin{at}fjd.es

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-{kappa}B (NF-{kappa}B) 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-{kappa}B in both VSMC and macrophages. In cultured VSMC, CD74 expression was induced by interferon {gamma} (IFN{gamma}). Incubation with an agonistic anti-CD74 antibody or with IFN{gamma} elicited MCP-1 expression, which was prevented by AKT and {gamma}-secretase inhibitors. Moreover, CD74 small-interfering RNA decreased NF-{kappa}B activation and MCP-1 production induced by IFN{gamma} 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.

KEYWORDS Atherosclerosis; Inflammation; Biomarkers; Carotid stenosis

Time for primary review: 13 days


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