Hypoxia increases LDL oxidation and expression of 15-lipoxygenase-2 in human macrophages.
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.


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.
Rydberg
Ellen Knutsen
EK
Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, SE 413 45 Göteborg, Sweden. ellen.rydberg@wlab.gu.se
Krettek
Alexandra
A
Ullström
Christina
C
Ekström
Karin
K
Svensson
Per-Arne
PA
Carlsson
Lena M S
LM
Jönsson-Rylander
Ann-Cathrine
AC
Hansson
Göran I
GI
McPheat
William
W
Wiklund
Olov
O
Ohlsson
Bertil G
BG
Hultén
Lillemor Mattsson
LM
D017398:Alternative Splicing / Q000235:genetics; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D001161:Arteriosclerosis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000235:genetics; D005091:Exons / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000201:enzymology* / Q000473:pathology*; D007150:Immunohistochemistry / Q000379:methods; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000201:enzymology*; D008323:Mammary Arteries / Q000502:physiology; D010084:Oxidation-Reduction; D017384:Sequence Deletion / Q000235:genetics
D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase