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

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
  • 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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: