on December 22, 2003
Published online before print December 22, 2003, doi: 10.1161/01.CIR.0000109201.72441.09
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Submitted on June 3, 2003
From the Department of Molecular Cardiovascular Research (A.S., U.Z., S.K., M.R., C.W.) and Department of Biochemistry and Molecular Cell Biology, Institute of Biochemistry (J.B., M.T.), Rheinisch-Westfälische Technische Hochschule, Aachen, Germany, and the Department of Medicine and Pathology (R.B.), Yale University, School of Medicine, New Haven, Conn. * To whom correspondence should be addressed. E-mail: cweber{at}ukaachen.de.
Background--Macrophage migration inhibitory factor (MIF), a cytokine that controls cell-mediated inflammatory responses, is upregulated in atherogenesis; however, its functional contribution to lesion development has not been evaluated. Methods and Results--We studied the role of MIF on neointima lesion formation after wire-induced injury of carotid arteries in apolipoprotein E-deficient (apoE-/-) mice. Immunohistochemistry revealed that MIF expression was detectable in endothelial cells before injury and upregulated in smooth muscle cells (SMCs) 24 hours after endothelial denudation. Three weeks after injury, MIF was predominantly found in endothelial cells and macrophage-derived foam cells. Neutralizing MIF with a monoclonal antibody resulted in a marked reduction of neointimal macrophages and inhibited transformation of macrophages into foam cells. Conversely, the content of SMCs and of collagen in the neointima were increased, amounting to a slight but not significant reduction in neointima and media size after 3 weeks of MIF monoclonal antibody treatment. Notably, serum levels of the cytokines IL-2, IL-4, IL-6, IL-10, and tumor necrosis factor were increased in MIF monoclonal antibody-treated mice. In vitro flow assays revealed that MIF pretreatment of aortic endothelium enhanced monocyte recruitment and that the monocyte arrest induced by oxidized LDL is mediated by endothelial MIF, as shown by monoclonal antibody inhibition. Conclusions--Inhibition of MIF resulted in a shift in the cellular composition of neointimal plaques toward a stabilized phenotype with reduced macrophage/foam cell content and increased SMC content. This might be attributable to a reduction of monocyte recruitment mediated by endothelial MIF.
Revised on September 11, 2003
Accepted on September 18, 2003
Stabilization of Atherosclerotic Plaques by Blockade of Macrophage Migration Inhibitory Factor After Vascular Injury in Apolipoprotein E-Deficient Mice
Andreas Schober MD,
Key words: inflammation • restenosis • plaque • hyperlipoproteinemia • endothelium
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