Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm

Abstract

Activation of the 5-lipoxygenase (5-LO) pathway leads to the biosynthesis of proinflammatory leukotriene lipid mediators. Genetic studies have associated 5-LO and its accessory protein, 5-LO-activating protein, with cardiovascular disease, myocardial infarction and stroke. Here we show that 5-LO-positive macrophages localize to the adventitia of diseased mouse and human arteries in areas of neoangiogenesis and that these cells constitute a main component of aortic aneurysms induced by an atherogenic diet containing cholate in mice deficient in apolipoprotein E. 5-LO deficiency markedly attenuates the formation of these aneurysms and is associated with reduced matrix metalloproteinase-2 activity and diminished plasma macrophage inflammatory protein-1α (MIP-1α; also called CCL3), but only minimally affects the formation of lipid-rich lesions. The leukotriene LTD4 strongly stimulates expression of MIP-1α in macrophages and MIP-2 (also called CXCL2) in endothelial cells. These data link the 5-LO pathway to hyperlipidemia-dependent inflammation of the arterial wall and to pathogenesis of aortic aneurysms through a potential chemokine intermediary route.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Constituents of the 5-LO pathway in Apoe−/− mouse aortas.
Figure 2: 5-LO in aneurysmal tissue.
Figure 3: 5-LO deficiency reduces aortic aneurysm formation and MMP-2 activity in Apoe−/− mice on Ath diet.
Figure 4: The 5-LO/leukotriene pathway mediates MIP-1α production in mouse.
Figure 5: 5-LO+ macrophages in areas of neoangiogenesis and LTD4 activates chemoattractant gene expression.
Figure 6: Model of 5-LO pathway participation in leukocyte recruitment and aneurysm formation.

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Ross, R. Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).

    CAS  Article  Google Scholar 

  2. Steinberg, D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nat. Med. 8, 1211–1217 (2002).

    CAS  Article  Google Scholar 

  3. Libby, P. Inflammation in atherosclerosis. Nature 420, 868–874 (2002).

    CAS  Google Scholar 

  4. Libby, P., Ridker, P.M. & Maseri, A. Inflammation and atherosclerosis. Circulation 105, 1135–1143 (2002).

    CAS  Article  Google Scholar 

  5. Samuelsson, B. Leukotrienes: mediators of immediate hypersensitivity actions and inflammation. Science 220, 568–575 (1983).

    CAS  Article  Google Scholar 

  6. Funk, C.D. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294, 1871–1875 (2001).

    CAS  Article  Google Scholar 

  7. De Caterina, R. et al. Leukotriene B4 production in human atherosclerotic plaques. Biomed. Biochim. Acta 47, S182–S185 (1988).

    CAS  PubMed  Google Scholar 

  8. Patrignani, P. et al. Release of contracting autacoids by aortae of normal and atherosclerotic rabbits. J. Cardiovasc. Pharmacol. 20, S208–S210 (1992).

    CAS  Article  Google Scholar 

  9. Spanbroek, R. et al. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proc. Natl. Acad. Sci. USA 100, 1238–1243 (2003).

    CAS  Article  Google Scholar 

  10. Mehrabian, M. et al. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ. Res. 91, 120–126 (2002).

    CAS  Article  Google Scholar 

  11. Dwyer, J.H. et al. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N. Engl. J. Med. 350, 29–37 (2004).

    CAS  Article  Google Scholar 

  12. Helgadottir, A. et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat. Genet. 36, 233–239 (2004).

    CAS  Article  Google Scholar 

  13. Aiello, R.J. et al. Leukotriene B4 receptor antagonism reduces monocytic foam cells in mice. Arterioscler. Thromb. Vasc. Biol. 22, 443–449 (2002).

    CAS  Article  Google Scholar 

  14. Subbarao, K. et al. Role of leukotriene B4 receptors in the development of atherosclerosis: potential mechanisms. Arterioscler. Thromb. Vasc. Biol. 24, 369–375 (2004).

    CAS  Article  Google Scholar 

  15. Chen, X.S. et al. cDNA cloning, expression, mutagenesis, intracellular localization and gene chromosomal assignment of mouse 5-lipoxygenase. J. Biol. Chem. 270, 17993–17999 (1995).

    CAS  Article  Google Scholar 

  16. Mehrabian, M. et al. Genetic locus in mice that blocks development of atherosclerosis despite extreme hyperlipidemia. Circ. Res. 89, 125–130 (2001).

    CAS  Article  Google Scholar 

  17. Hart, D.N. Dendritic cells: Unique leukocyte populations which control the primary immune response. Blood 90, 3245–3287 (1997).

    CAS  PubMed  Google Scholar 

  18. Silence, J., Lupu, F., Collen, D. & Lijnen, H.R. Persistence of atherosclerotic plaque but reduced aneurysm formation in mice with stromelysin-1 (MMP-3) gene inactivation. Arterioscler. Thromb. Vasc. Biol. 21, 1440–1445 (2001).

    CAS  Article  Google Scholar 

  19. Daugherty, A., Manning, M.W. & Cassis, L.A. Antagonism of AT2 receptors augments angiotensin II–induced abdominal aortic aneurysms and atherosclerosis. Br. J. Pharmacol. 134, 865–870 (2001).

    CAS  Article  Google Scholar 

  20. Bruemmer, D. et al. Angiotensin II–accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice. J. Clin. Invest. 112, 1318–1331 (2003).

    CAS  Article  Google Scholar 

  21. Longo, G.M. et al. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J. Clin. Invest. 110, 625–632 (2002).

    CAS  Article  Google Scholar 

  22. Lötzer, K. et al. Differential leukotriene receptor expression and calcium responses in endothelial cells and macrophages indicate 5-lipoxygenase-dependent circuits of inflammation and atherogenesis. Arterioscler. Thromb. Vasc. Biol. 23, e32–e36 (2003).

    Article  Google Scholar 

  23. Daugherty, A. & Cassis, L.A. Mouse models of abdominal aortic aneurysms. Arterioscler. Thromb. Vasc. Biol. 24, 429–434 (2004).

    CAS  Article  Google Scholar 

  24. Manning, M.W., Cassis, L.A., Huang. J., Szilvassy, S.J. & Daugherty, A. Abdominal aortic aneurysms: fresh insights from a novel animal model of the disease. Vasc. Med. 7, 45–54 (2002).

    Article  Google Scholar 

  25. Sinha, S. & Frishman, W.H. Matrix metalloproteinases and abdominal aortic aneurysms: a potential therapeutic target. J. Clin. Pharmacol. 38, 1077–1088 (1998).

    CAS  PubMed  Google Scholar 

  26. Werb, Z. ECM and cell surface proteolysis: regulating cellular ecology. Cell 91, 439–442 (1997).

    CAS  Article  Google Scholar 

  27. Zhou, X., Paulsson, G., Stemme, S. & Hansson, G.K. Hypercholesterolemia is associated with a T helper (Th) 1/Th2 switch of the autoimmune response in atherosclerotic apoE-knockout mice. J. Clin. Invest. 101, 1717–1725 (1998).

    CAS  Article  Google Scholar 

  28. Houtkamp, M.A., de Boer, O.J., van der Loos, C.M., van der Wal, A.C. & Becker, A.E. Adventitial infiltrates associated with advanced atherosclerotic plaques: structural organization suggests generation of local humoral immune responses. J. Pathol. 193, 263–269 (2001).

    CAS  Article  Google Scholar 

  29. Kumamoto, M., Nakashima, Y. & Sueishi, K. Intimal neovascularization in human coronary atherosclerosis: its origin and pathophysiological significance. Hum. Pathol. 26, 450–456 (1995).

    CAS  Article  Google Scholar 

  30. Dollery, C.M. et al. Neutrophil elastase in human atherosclerotic plaques: production by macrophages. Circulation 107, 2829–2836 (2003).

    CAS  Article  Google Scholar 

  31. Hansson, G.K., Libby, P., Schonbeck, U. & Yan, Z.Q. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ. Res. 91, 281–291 (2002).

    CAS  Article  Google Scholar 

  32. Lusis, A.J. Atherosclerosis. Nature 407, 233–241 (2000).

    CAS  Article  Google Scholar 

  33. Kuhel, D.G., Zhu, B., Witte, D.P. & Hui, D.Y. Distinction in genetic determinants for injury-induced neointimal hyperplasia and diet-induced atherosclerosis in inbred mice. Arterioscler. Thromb. Vasc. Biol. 22, 955–960 (2002).

    CAS  Article  Google Scholar 

  34. Shi, W. et al. Genetic backgrounds but not sizes of atherosclerotic lesions determine medial destruction in the aortic root of apolipoprotein E–deficient mice. Arterioscler. Thromb. Vasc. Biol. 23, 1901–1906 (2003).

    CAS  Article  Google Scholar 

  35. Galis, Z.S. & Khatri, J.J. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ. Res. 90, 251–262 (2002).

    CAS  Article  Google Scholar 

  36. Ward, M.R., Pasterkamp, G., Yeung, A.C. & Borst, C. Arterial remodeling. Mechanisms and clinical implications. Circulation 102, 1186–1191 (2000).

    CAS  Article  Google Scholar 

  37. Baggiolini, M. Chemokines and leukocyte traffic. Nature 392, 565–568 (1998).

    CAS  Article  Google Scholar 

  38. Springer, T.A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76, 301–314 (1994).

    CAS  Article  Google Scholar 

  39. Mach, F. et al. Differential expression of three T lymphocyte–activating CXC chemokines by human atheroma-associated cells. J. Clin. Invest. 104, 1041–1050 (1999).

    CAS  Article  Google Scholar 

  40. Apostolopoulos, J., Davenport, P. & Tipping, P.G. Interleukin-8 production by macrophages from atheromatous plaques. Arterioscler. Thromb. Vasc. Biol. 16, 1007–1012 (1996).

    CAS  Article  Google Scholar 

  41. Koch, A.E. et al. Enhanced production of the chemotactic cytokines interleukin-8 and monocyte chemoattractant protein-1 in human abdominal aneurysms. Am. J. Pathol. 142, 1423–1431 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Gerszten, R.E. et al. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature 22, 718–723 (1999).

    Article  Google Scholar 

  43. Pelus, L.M., Bian, H., King, A.G. & Fukuda, S. Neutrophil-derived MMP-9 mediates synergistic mobilization of hematopoietic stem and progenitor cells by the combination of G-CSF and the chemokines GROβ/CXCL2 and GROβT/CXCL2δ4. Blood 103, 110–119 (2004).

    CAS  Article  Google Scholar 

  44. Boisvert, W.A., Santiago, R., Curtiss, L.K. & Terkeltaub, R.A. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J. Clin. Invest. 101, 353–363 (1998).

    CAS  Article  Google Scholar 

  45. Luster, A.D. Chemokines—chemotactic cytokines that mediate inflammation. N. Engl. J. Med. 338, 436–445 (1998).

    CAS  Article  Google Scholar 

  46. Chen, X.S., Sheller, J.R., Johnson, E.N. & Funk, C.D. Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene. Nature 372, 179–182 (1994).

    CAS  Article  Google Scholar 

  47. Goulet, J.L., Snouwaert, J.N., Latour, A.M., Coffman, T.M. & Koller, B.H. Altered inflammatory responses in leukotriene-deficient mice. Proc. Natl. Acad. Sci. USA 91, 12852–12856 (1994).

    CAS  Article  Google Scholar 

  48. Tangirala, R.K., Rubin, E.M. & Palinski, W. Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor–deficient and apolipoprotein E–deficient mice. J. Lipid Res. 36, 2320–2328 (1995).

    CAS  PubMed  Google Scholar 

  49. Cyrus, T. et al. Effect of low-dose aspirin on vascular inflammation, plaque stability, and atherogenesis in low-density lipoprotein receptor-deficient mice. Circulation 106, 1282–1287 (2002).

    CAS  Article  Google Scholar 

  50. Basso, K. et al. Gene expression profiling of hairy cell leukemia reveals a phenotype related to memory B cells with altered expression of chemokine and adhesion receptors. J. Exp. Med. 199, 59–68 (2004).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank J.A. Lawson for technical support with LC–MS/MS assays; A.J. Cucchiara for assistance with statistical analysis; M. Hildner and G. Weber for technical assistance with microarray analyses, real-time RT-PCR and immunohistochemical morphometry; D. Marchadier and S. Jahn for lipoprotein profile analyses; J. Ventre, T. Dobber and J. Menke for insulin measurements; and B. Koller for 5-LO−/− mice. This work was supported by grants from the National Institutes of Health (HL53558 to C.D.F.; HL70128 and HL55323 to D.J.R.), the Canadian Institutes of Health Research (MOP-67146 to C.D.F.), the Deutsche Forschungsgemeinschaft (Ha 1083/13-1/13-2/13-3/13-4/12-5/12-6), the European Union research network (QLG1-CT-2001-01521 to A.J.R.H.), the Interdisziplinäre Zentrum für Klinische Forschung Jena and the Singulair Medical School Program (to A.J.R.H.), and by an American Heart Association postdoctoral fellowship (0225369U to L.Z.). C.D.F. holds a Canada Research Chair in Molecular, Cellular and Physiological Medicine.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Colin D Funk.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

5-LO expression in bone marrow cells and peritoneal macrophages. (PDF 127 kb)

Supplementary Fig. 2

Genotype analysis of mice. (PDF 108 kb)

Supplementary Table 1

LC/MS/MS quantitation of leukotrienes extracted from aortas of Apoe−/− and Apoe−/− Alox5−/− mice. (PDF 24 kb)

Supplementary Table 2

2a. Effect of 5-LO deficiency on aortic lipid deposition in mouse models of atherosclerosis. (PDF 27 kb)

2b. Lesion quantitation at the aortic root in mouse models of atherosclerosis.

2c. Effect of 5-LO deficiency on plaque size and Intima/Media ratio in apoE-/- mice.

Supplementary Table 3

Plasma total cholesterol levels in mouse models of atherosclerosis. (PDF 22 kb)

Supplementary Table 4

Plasma insulin levels in mouse models of atherosclerosis. (PDF 23 kb)

Supplementary Table 5

Effect of 5-LO deficiency on plasma cytokine and chemokine levels in mouse models of atherosclerosis. (PDF 24 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zhao, L., Moos, M., Gräbner, R. et al. The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nat Med 10, 966–973 (2004). https://doi.org/10.1038/nm1099

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1099

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing