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

Nature Medicine volume 10, pages 966–973 (2004)Cite this article

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.

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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.

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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.

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Authors and Affiliations

  1. Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, 19104-6160, USA

    Lei Zhao, Frédérique Pédrono, Jinjin Fan, Daniel J Rader & Colin D Funk

  2. Institute for Vascular Medicine, Friedrich-Schiller University of Jena, Bachstrasse 18, Jena, 07743, Germany

    Michael P W Moos, Rolf Gräbner, Brigitte Kaiser, Nicole John, Sandra Schmidt, Rainer Spanbroek, Katharina Lötzer & Andreas J R Habenicht

  3. Departments of Physiology and Biochemistry, Queen's University, Kingston, K7L 3N6, Ontario, Canada

    Frédérique Pédrono & Colin D Funk

  4. Department of Cardiovascular Diseases, Merck & Company, Rahway, 07065, New Jersey, USA

    Li Huang, Jisong Cui & Jilly F Evans

  5. Department of Medicine, University of Pennsylvania, Philadelphia, 19104-6160, Pennsylvania, USA

    Daniel J Rader & Colin D Funk

  6. Department of Pharmacology, University of Pennsylvania, Philadelphia, 19104-6160, Pennsylvania, USA

    Colin D Funk

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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)

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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

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