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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2040.)
© 2004 American Heart Association, Inc.

Vascular Biology

Hypoxia Increases LDL Oxidation and Expression of 15-Lipoxygenase-2 in Human Macrophages

Ellen Knutsen Rydberg; Alexandra Krettek; Christina Ullström; Karin Ekström; Per-Arne Svensson; Lena M.S. Carlsson; Ann-Cathrine Jönsson-Rylander; Göran I. Hansson; William McPheat; Olov Wiklund; Bertil G. Ohlsson; Lillemor Mattsson Hultén

From the Wallenberg Laboratory for Cardiovascular Research (E.K.R., A.K., C.U., K.E., O.W., B.G.O., L.M.H.); the Research Center for Endocrinology & Metabolism (P.-A.S., L.M.S.C.), Sahlgrenska University Hospital, Göteborg, Sweden; and Molecular Pharmacology (A.-C.J.-R, W.M.) and DMPK, Bioanalytical Chemistry (G.I.H.) AstraZeneca R&D, Mölndal, Sweden.

Correspondence to Ellen K. Rydberg, Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, SE 413 45 Göteborg, Sweden. E-mail ellen.rydberg{at}wlab.gu.se

Objective— Macrophage-mediated oxidation of low-density lipoprotein (LDL) by enzymes, such as the lipoxygenases, is considered of major importance for the formation of oxidized LDL during atherogenesis. Macrophages have been identified in hypoxic areas in atherosclerotic plaques.

Methods and Results— To investigate the role of hypoxia in macrophage-mediated LDL oxidation, we incubated human monocyte-derived macrophages with LDL under normoxic (21% O₂) or hypoxic (0% O₂) conditions. The results showed that hypoxic macrophages oxidized LDL to a significantly higher extent than normoxic cells. Interestingly, the mRNA and protein expression of 15-lipoxygenase-2 (15-LOX-2) as well as the activity of this enzyme are elevated in macrophages incubated at hypoxia. Both the unspliced 15-LOX-2 and the spliced variant 15-LOX-2sv-a are found in macrophages. In addition, 15-LOX-2 was identified in carotid plaques in some macrophage-rich areas but was only expressed at low levels in nondiseased arteries.

Conclusions— In summary, these observations show for the first time that 15-LOX-2 is expressed in hypoxic macrophages and in atherosclerotic plaques and suggest that 15-LOX-2 may be one of the factors involved in macrophage-mediated LDL oxidation at hypoxia.

Macrophage-mediated low-density lipoprotein oxidation and hypoxia are mechanisms involved in atherogenesis. Compared with normoxic macrophages, hypoxic-treated cells increased low-density lipoprotein oxidation and the protein expression as well as the activity of 15-lipoxygenase-2 (15-LOX-2). 15-LOX-2 was also identified in human carotid plaques. This suggests that 15-LOX-2 may be involved in atherogenesis.

Key Words: atherosclerosis • macrophages • hypoxia • oxidized-LDL • 15-lipoxygenase-2

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