Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis

doi:10.1073/pnas.242716099

Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis

^*Institute for Vascular Medicine, Friedrich-Schiller-University of Jena, Nordhäuserstrasse 78, 99089 Erfurt, Germany; ^§Department of Cardio-Thoracic and Vascular Surgery, Friedrich-Schiller-University of Jena, Bachstrasse 18, 07740 Jena, Germany; ^¶Department of Pathology, Louisiana State University Medical Center, New Orleans, LA 70112-1393; ^‖Institute for Atherosclerosis Research, Domagkstrasse 3, 48149 Münster, Germany; ^**Department of Medicine, Division of Cardiology, University of Heidelberg Medical School, Bergheimerstrasse 58, 69115 Heidelberg, Germany; ^‡‡Institute of Biochemistry, Humboldt University Berlin, Monbijoustrasse 2, 10115 Berlin, Germany; and ^††Karolinska Institute, Department of Medical Biochemistry and Biophysics, Division of Chemistry II, S-171 77 Stockholm, Sweden

Contributed by Bengt Samuelsson

Abstract

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.

arachidonic acid cascade‖coronary heart disease

Footnotes

↵ † R.S., R.G., and K.L. contributed equally to this work.
↵ ‡ To whom correspondence should be addressed. E-mail: spanbroek{at}zmkh.ef.uni-jena.de.
Abbreviations:

AAO,

atherosclerosis of the aorta;

AHA,

American Heart Association;

CAD,

carotid artery disease;

CHD,

coronary heart disease;

DC,

dendritic cell;

ECs,

endothelial cells;

LO,

lipoxygenase;

FLAP,

5-LO activating protein;

GAPDH,

glyceraldehyde-3-phosphate dehydrogenase;

LDL,

low-density lipoprotein;

LT,

leukotriene;

LT-R,

LT receptor;

SMCs,

smooth muscle cells