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.

• Authors: Lei 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
• Journal: Nature medicine (Nat Med) Vol. 10 Issue 9 Pg. 966-73 (Sep 2004) ISSN: 1078-8956 [Print] United States
• PMID: 15322539 (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