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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-1alpha (MIP-1alpha; also called CCL3), but only minimally affects the formation of lipid-rich lesions. The leukotriene LTD(4) strongly stimulates expression of MIP-1alpha 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.
AuthorsLei Zhao, Michael P W Moos, Rolf Gräbner, Frédérique Pédrono, Jinjin Fan, Brigitte Kaiser, Nicole John, Sandra Schmidt, Rainer Spanbroek, Katharina Lötzer, Li Huang, Jisong Cui, Daniel J Rader, Jilly F Evans, Andreas J R Habenicht, Colin D Funk
JournalNature medicine (Nat Med) Vol. 10 Issue 9 Pg. 966-73 (Sep 2004) ISSN: 1078-8956 [Print] United States
PMID15322539 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • 5-Lipoxygenase-Activating Proteins
  • ALOX5AP protein, human
  • Alox5ap protein, mouse
  • CCL2 protein, human
  • CXCL1 protein, human
  • Carrier Proteins
  • Chemokine CCL2
  • Chemokine CCL3
  • Chemokine CCL4
  • Chemokine CXCL1
  • Chemokines, CXC
  • Cholates
  • Cytokines
  • DNA Primers
  • Intercellular Signaling Peptides and Proteins
  • Leukotrienes
  • Macrophage Inflammatory Proteins
  • Membrane Proteins
  • RNA
  • Leukotriene D4
  • Arachidonate 5-Lipoxygenase
  • Matrix Metalloproteinase 2
Topics
  • 5-Lipoxygenase-Activating Proteins
  • Analysis of Variance
  • Animals
  • Aortic Aneurysm, Abdominal (etiology)
  • Arachidonate 5-Lipoxygenase (metabolism)
  • Blotting, Western
  • Carrier Proteins (metabolism)
  • Chemokine CCL2 (blood)
  • Chemokine CCL3
  • Chemokine CCL4
  • Chemokine CXCL1
  • Chemokines, CXC (metabolism)
  • Cholates
  • Connective Tissue (metabolism)
  • Cytokines (blood)
  • DNA Primers
  • Diet, Atherogenic
  • Gene Expression Regulation
  • Histological Techniques
  • Humans
  • Hyperlipidemias (complications)
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins (metabolism)
  • Leukotriene D4 (metabolism)
  • Leukotrienes (biosynthesis)
  • Macrophage Inflammatory Proteins (metabolism)
  • Macrophages (metabolism)
  • Matrix Metalloproteinase 2 (metabolism)
  • Membrane Proteins (metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic (metabolism)
  • RNA (genetics)
  • Reverse Transcriptase Polymerase Chain Reaction

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