Details

Autor(en) / Beteiligte

• Hultén, L M
• Olson, F J
• Aberg, H
• Carlsson, J
• Karlström, L
• Borén, J
• Fagerberg, B
• Wiklund, O

Titel

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

Ist Teil von

• European journal of clinical investigation, 2010-01, Vol.40 (1), p.11-17

Ort / Verlag

England

Erscheinungsjahr

2010

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 1alpha (HIF-1alpha). 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-1alpha siRNA or control siRNA before extraction of RNA and medium analysis. 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-1alpha stabilizer dimethyloxalylglycine. Knockdown of HIF-1alpha significantly decreased production of the 15-LOX-2 enzyme products 12- and 15-hydroxyeicosatetraenoic acid. In carotid plaques, HIF-1alpha staining correlated with staining for 15-LOX-2. These results demonstrate that 15-LOX-2 is highly expressed in human plaques and is correlated with the presence of macrophages and HIF-1alpha. 15-LOX-2 enzyme activity can be modulated by HIF-1alpha. Thus, increased expression of 15-LOX-2 in macrophages in hypoxic atherosclerotic plaque may enhance inflammation and the recruitment of inflammatory cells.