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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:84.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Accumulation of Myeloperoxidase-Positive Neutrophils in Atherosclerotic Lesions in LDLR^–/– Mice

Marcella van Leeuwen; Marion J.J. Gijbels; Adriaan Duijvestijn; Marjan Smook; Marie José van de Gaar; Peter Heeringa; Menno P.J. de Winther; Jan Willem Cohen Tervaert

From the Departments of Clinical and Experimental Immunology (M.v.L., A.D., M.S., M.J.v.d.G., P.H., J.W.C.T.), Molecular Genetics (M.J.J.G., M.P.J.d.W.), and Pathology (M.J.J.G.), Cardiovascular Research Institute Maastricht, Maastricht University; and the Department of Pathology and Laboratory Medicine (P.H.), Medical Biology Section, University Medical Center Groningen, Groningen, the Netherlands.

Correspondence to M.P.J. de Winther, Department of Molecular Genetics, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. E-mail dewinther{at}gen.unimaas.nl

Abstract

Objective— Atherosclerosis is a chronic inflammatory disease in which the immune system plays an important role. Neutrophils have not been thoroughly studied in the context of atherogenesis. Here, we investigated neutrophils in the development of murine atherosclerotic lesions.

Methods and Results— LDLR^–/– mice were given a high-fat diet for different time periods and subsequently atherosclerotic lesions were studied by immunohistochemistry. Staining with anti–Ly-6G monoclonal antibody, a specific marker for neutrophils, revealed a marked accumulation of neutrophils during atherosclerosis development. Neutrophils were observed in the lesion, attached to the cap, and in the arterial adventitia. In addition, at some sites, neutrophil accumulation colocalized with endothelial E-selectin expression. Immunofluorescence double staining with anti-myeloperoxidase and anti–Ly-6G antibodies demonstrated the presence of myeloperoxidase in atherosclerotic lesions and its colocalization with neutrophils. After introducing the high-fat diet, levels of circulating myeloperoxidase in plasma strongly increased, with a peak at 6 weeks and a subsequent decrease to almost normal levels after 16 weeks of diet.

Conclusions— We here demonstrate for the first time the presence of neutrophils and myeloperoxidase in murine atherosclerotic lesions. As a major cell type in inflammatory responses the neutrophil may also be an important mediator in the development of atherosclerosis.

We identified myeloperoxidase-positive neutrophils in mouse atherosclerotic lesions. Although neutrophils were not detected in early lesions, they were abundantly present in more advanced stages. In addition, circulating myeloperoxidase levels were strongly increased by high-fat feeding of the mice. Therefore, neutrophils should be considered as a potential important cellular mediator in atherogenesis.

Key Words: atherosclerosis • neutrophil • myeloperoxidase • immunohistochemistry • LDLR^–/– mice

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