Nature Medicine
10, 966 - 973 (2004)
Published online: 22 August 2004; | doi:10.1038/nm1099
The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysmLei Zhao1, Michael P W Moos2, Rolf Gräbner2, Frédérique Pédrono1, 3, Jinjin Fan1, Brigitte Kaiser2, Nicole John2, Sandra Schmidt2, Rainer Spanbroek2, Katharina Lötzer2, Li Huang4, Jisong Cui4, Daniel J Rader1, 5, Jilly F Evans4, Andreas J R Habenicht2
& Colin D Funk1, 3, 5, 61
Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA. 2
Institute for Vascular Medicine, Friedrich-Schiller University of Jena, Bachstrasse 18, 07743 Jena, Germany. 3
Departments of Physiology and Biochemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada. 4
Department of Cardiovascular Diseases, Merck & Company, Rahway, New Jersey 07065, USA. 5
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA. 6
Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.
Correspondence should be addressed to Colin D Funk funkc@post.queensu.caActivation 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-1 (MIP-1; also called CCL3), but only minimally affects the formation of lipid-rich lesions. The leukotriene LTD4 strongly stimulates expression of MIP-1 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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