Journal
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
Volume 40, Issue 1, Pages 11-17Publisher
WILEY-BLACKWELL PUBLISHING, INC
DOI: 10.1111/j.1365-2362.2009.02223.x
Keywords
15-lipoxygenase-2; carotid plaques; human; hypoxia; macrophages
Funding
- Swedish Heart and Lung Foundation, Stockholm
- Swedish Research Council, Stockholm
- Swedish Foundation for Strategic Research, Stockholm, AstraZeneca, Molndal, Sweden
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P>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 1 alpha (HIF-1 alpha). 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-1 alpha 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-1 alpha stabilizer dimethyloxalylglycine. Knockdown of HIF-1 alpha significantly decreased production of the 15-LOX-2 enzyme products 12- and 15-hydroxyeicosatetraenoic acid. In carotid plaques, HIF-1 alpha 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-1 alpha. 15-LOX-2 enzyme activity can be modulated by HIF-1 alpha. 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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