Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis.
Oxidation products of low-density lipoproteins have been suggested to promote inflammation during atherogenesis, and reticulocyte-type 15-lipoxygenase has been implicated to mediate this oxidation. In addition, the 5-lipoxygenase cascade leads to formation of leukotrienes, which exhibit strong proinflammatory activities in cardiovascular tissues. Here, we studied both lipoxygenase pathways in human atherosclerosis. The 5-lipoxygenase pathway was abundantly expressed in arterial walls of patients afflicted with various lesion stages of atherosclerosis of the aorta and of coronary and carotid arteries. 5-lipoxygenase localized to macrophages, dendritic cells, foam cells, mast cells, and neutrophilic granulocytes, and the number of 5-lipoxygenase expressing cells markedly increased in advanced lesions. By contrast, reticulocyte-type 15-lipoxygenase was expressed at levels that were several orders of magnitude lower than 5-lipoxygenase in both normal and diseased arteries, and its expression could not be related to lesion pathology. Our data support a model of atherogenesis in which 5-lipoxygenase cascade-dependent inflammatory circuits consisting of several leukocyte lineages and arterial wall cells evolve within the blood vessel wall during critical stages of lesion development. They raise the possibility that antileukotriene drugs may be an effective treatment regimen in late-stage disease.
Spanbroek
Rainer
R
Institute for Vascular Medicine, Friedrich-Schiller-University of Jena, Nordhäuserstrasse 78, 99089 Erfurt, Germany. spanbroek@zmkh.ef.uni-jena.de
Grabner
Rolf
R
Lotzer
Katharina
K
Hildner
Markus
M
Urbach
Anja
A
Ruhling
Katharina
K
Moos
Michael P W
MP
Kaiser
Brigitte
B
Cohnert
Tina U
TU
Wahlers
Thorsten
T
Zieske
Arthur
A
Plenz
Gabriele
G
Robenek
Horst
H
Salbach
Peter
P
Kuhn
Hartmut
H
Radmark
Olof
O
Samuelsson
Bengt
B
Habenicht
Andreas J R
AJ
D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D001011:Aorta / Q000201:enzymology; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis / Q000378:metabolism*; D001158:Arteries / Q000201:enzymology*; D001161:Arteriosclerosis / Q000473:pathology; D019070:Cell Lineage; D004730:Endothelium, Vascular / Q000201:enzymology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007700:Kinetics; D007962:Leukocytes / Q000201:enzymology; D008264:Macrophages / Q000201:enzymology; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012156:Reticulocytes / Q000201:enzymology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase; D012313:RNA; D012333:RNA, Messenger; C067980:CD68 antigen, human; D000097382:CD68 Molecule