Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability
- Hong Qiu*,
- Anders Gabrielsen†,
- Hanna E. Agardh†,
- Min Wan*,
- Anders Wetterholm*,
- Chi-Huey Wong‡,
- Ulf Hedin§,
- Jesper Swedenborg§,
- Göran K. Hansson†,
- Bengt Samuelsson*,¶,
- Gabrielle Paulsson-Berne†, and
- Jesper Z. Haeggström*,¶
- *Department of Medical Biochemistry and Biophysics, Division of Chemistry II, Karolinska Institutet, S-171 77 Stockholm, Sweden;
- §Department of Vascular Surgery and
- †Center for Molecular Medicine and Department of Medicine, Karolinska University Hospital, S-171 76 Stockholm, Sweden; and
- ‡Department of Chemistry, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037
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Contributed by Bengt Samuelsson, March 28, 2006
Abstract
Leukotrienes (LT) are a group of proinflammatory lipid mediators that are implicated in the pathogenesis and progression of atherosclerosis. Here we report that mRNA levels for the three key proteins in LTB4 biosynthesis, namely 5-lipoxygenase (5-LO), 5-LO-activating protein (FLAP), and LTA4 hydrolase (LTA4H), are significantly increased in human atherosclerotic plaque (n = 72) as compared with healthy controls (n = 6). Neither LTC4 synthase nor any of the LT receptors exhibits significantly increased mRNA levels. Immunohistochemical staining revealed abundant expression of 5-LO, FLAP, and LTA4H protein, colocalizing in macrophages of intimal lesions. Human lesion tissue converts arachidonic acid into significant amounts of LTB4, and a selective, tight-binding LTA4H inhibitor can block this activity. Furthermore, expression of 5-LO and LTA4H, but not FLAP, is increased in patients with recent or ongoing symptoms of plaque instability, and medication with warfarin correlates with increased levels of FLAP mRNA. In contrast to human plaques, levels of 5-LO mRNA are not significantly increased in plaque tissues from two atherosclerosis-prone mouse strains, and mouse plaques exhibit segregated cellular expression of LTA4H and 5-LO as well as strong increases of CysLT1 and CysLT2 mRNA. These discrepancies indicate that phenotypic changes in the synthesis and action of LT in specific mouse models of atherosclerosis should be cautiously translated into human pathology. The abundant expression of LTA4H and correlation with plaque instability identify LTA4H as a potential target for pharmacological intervention in treatment of human atherosclerosis.
Footnotes
- ¶To whom correspondence may be addressed. E-mail: jesper.haeggstrom{at}mbb.ki.se or bengt.samuelsson{at}mbb.ki.se
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Author contributions: H.Q., A.G., A.W., and J.Z.H. designed research; H.Q., A.G., H.E.A., M.W., and A.W. performed research; C.-H.W. synthesized the LTA4H inhibitor; U.H., J.S., G.P.-B., and G.K.H. provided Biobank materials; C.-H.W., U.H., J.S., and G.P.-B. contributed new reagents/analytic tools; H.Q., A.G., M.W., A.W., U.H., J.S., G.K.H., B.S., G.P.-B., and J.Z.H. analyzed data; and H.Q. and J.Z.H. wrote the paper.
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Conflict of interest statement: No conflicts declared.
- Abbreviations:
- LT,
- leukotriene;
- CysLT,
- cysteinyl-LT receptor;
- 5-LO,
- 5-lipoxygenase;
- LTA4H,
- LTA4 hydrolase;
- FLAP,
- 5-LO-activating protein;
- LTC4S,
- LTC4 synthase;
- LDLR,
- low-density lipoprotein receptor;
- ApoE,
- apolipoprotein E;
- EIA,
- enzyme immunoassay.
Abbreviations:
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Freely available online through the PNAS open access option.
- © 2006 by The National Academy of Sciences of the USA
