ABSTRACT
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-kappaB (NF-kappaB) 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-kappaB in both VSMC and macrophages. In cultured VSMC, CD74 expression was induced by interferon gamma (IFNgamma). Incubation with an agonistic anti-CD74 antibody or with IFNgamma elicited MCP-1 expression, which was prevented by AKT and gamma-secretase inhibitors. Moreover, CD74 small-interfering RNA decreased NF-kappaB activation and MCP-1 production induced by IFNgamma 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.
Subject(s)
Antigens, Differentiation, B-Lymphocyte/metabolism , Carotid Arteries/immunology , Carotid Stenosis/immunology , Histocompatibility Antigens Class II/metabolism , Inflammation Mediators/metabolism , Inflammation/immunology , Muscle, Smooth, Vascular/immunology , Myocytes, Smooth Muscle/immunology , Antigens, Differentiation, B-Lymphocyte/blood , Antigens, Differentiation, B-Lymphocyte/genetics , Biomarkers/metabolism , Carotid Arteries/pathology , Carotid Arteries/surgery , Carotid Stenosis/pathology , Carotid Stenosis/surgery , Case-Control Studies , Cells, Cultured , Chemokine CCL2/metabolism , Endarterectomy, Carotid , Fibrosis , Histocompatibility Antigens Class II/blood , Histocompatibility Antigens Class II/genetics , Humans , Inflammation/pathology , Inflammation Mediators/blood , Interferon-gamma/metabolism , Leukocytes, Mononuclear/immunology , Macrophages/immunology , Muscle, Smooth, Vascular/pathology , Muscle, Smooth, Vascular/surgery , Myocytes, Smooth Muscle/pathology , NF-kappa B/metabolism , RNA Interference , Recombinant Proteins/metabolism , Severity of Illness Index , Time Factors , Transfection , Tumor Necrosis Factor-alpha/metabolism , Tunica Intima/immunology , Tunica Media/immunology , Up-RegulationABSTRACT
Arteriogenesis, the enlargement of collateral vessels, seems a promising new target to improve blood flow to ischemic regions in patients suffering from cardiovascular conditions. With the growing knowledge of the mechanisms involved in arteriogenesis and the factors that influence the process, an increasing number of clinical trials are being performed to stimulate arteriogenesis, providing more insight in therapeutic opportunities for arteriogenesis. The expression of growth factors and the cooperation of surrounding and infiltrating cells seem to be essential in orchestrating the complex processes during arteriogenesis. In this review, we will discuss the regulating mechanisms of arteriogenesis, including the role of growth factors and different cell types and their implementation in a clinical setting. Furthermore, individual differences in the arteriogenic response will be considered, in light of the effect this will have on the success of therapeutic strategies to improve blood flow to ischemic tissue.
