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15-Lipoxygenase-2 is expressed in macrophages in human carotid plaques and regulated by hypoxia-inducible factor-1 alpha

Journal article
Authors Lillemor Mattsson Hultén
Fredrik J. Olson
Hanna Åberg
Jonas Carlsson
Lars Karlström
Jan Borén
Björn Fagerberg
Olov Wiklund
Published in European Journal of Clinical Investigation
Volume 40
Issue 1
Pages 11-17
ISSN 1365-2362
Publication year 2010
Published at Wallenberg Laboratory
Institute of Medicine
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Institute of Medicine, Department of Molecular and Clinical Medicine
Institute of Clinical Sciences
Pages 11-17
Language en
Links dx.doi.org/10.1111/j.1365-2362.2009...
Keywords 15-lipoxygenase-2, carotid plaques, human, hypoxia, macrophages
Subject categories Cell and Molecular Biology

Abstract

Background Macrophages are prominent in hypoxic areas of atherosclerotic lesions and their secreted cytokines, growth factors and activity of enzymes are involved in atherogenesis. Previously, we showed that 15-lipoxygenase (LOX)-2 is expressed in human monocyte-derived macrophages and that hypoxia increases 15-LOX-2 expression and secretion of pro-inflammatory molecules. Here we investigated whether human carotid plaque macrophages express 15-LOX-2 and whether its expression in macrophages is regulated by hypoxia through hypoxia-inducible factor 1α (HIF-1α). Materials and methods Carotid plaques from 47 patients with high-grade symptomatic carotid artery stenosis were analysed using immunohistochemistry, and stained areas were quantified by digital image analysis. Carotid plaque macrophages were isolated with anti-CD14 immunobeads using an immunomagnetic bead technique. Primary macrophages were transfected with HIF-1α siRNA or control siRNA before extraction of RNA and medium analysis. Results In paired tissue sections, the extent of staining for CD68 correlated with staining for 15-LOX-2 but not for 15-LOX-1. In carotid plaque macrophages isolated with anti-CD14 immunobeads, 15-LOX-2 mRNA was expressed at high levels. In primary macrophages, 15-LOX-2 expression was significantly increased by incubation with the HIF-1α stabilizer dimethyloxalylglycine. Knockdown of HIF-1α significantly decreased production of the 15-LOX-2 enzyme products 12- and 15-hydroxyeicosatetraenoic acid. In carotid plaques, HIF-1α staining correlated with staining for 15-LOX-2. Conclusions These results demonstrate that 15-LOX-2 is highly expressed in human plaques and is correlated with the presence of macrophages and HIF-1α. 15-LOX-2 enzyme activity can be modulated by HIF-1α. Thus, increased expression of 15-LOX-2 in macrophages in hypoxic atherosclerotic plaque may enhance inflammation and the recruitment of inflammatory cells.

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