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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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5-Lipoxygenase-Activating Proteins
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Analysis of Variance
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Animals
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Aortic Aneurysm, Abdominal / etiology*
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Arachidonate 5-Lipoxygenase / metabolism*
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Blotting, Western
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Carrier Proteins / metabolism
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Chemokine CCL2 / blood
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Chemokine CCL3
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Chemokine CCL4
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Chemokine CXCL1
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Chemokines, CXC / metabolism
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Cholates
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Connective Tissue / metabolism
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Cytokines / blood
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DNA Primers
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Diet, Atherogenic
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Gene Expression Regulation*
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Histological Techniques
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Humans
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Hyperlipidemias / complications*
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Immunohistochemistry
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Intercellular Signaling Peptides and Proteins / metabolism
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Leukotriene D4 / metabolism
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Leukotrienes / biosynthesis*
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Macrophage Inflammatory Proteins / metabolism
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Macrophages / metabolism*
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Matrix Metalloproteinase 2 / metabolism
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Neovascularization, Pathologic / metabolism
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RNA / genetics
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Reverse Transcriptase Polymerase Chain Reaction
Substances
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5-Lipoxygenase-Activating Proteins
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ALOX5AP protein, human
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Alox5ap protein, mouse
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CCL2 protein, human
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CXCL1 protein, human
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Carrier Proteins
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Chemokine CCL2
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Chemokine CCL3
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Chemokine CCL4
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Chemokine CXCL1
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Chemokines, CXC
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Cholates
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Cytokines
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DNA Primers
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Intercellular Signaling Peptides and Proteins
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Leukotrienes
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Macrophage Inflammatory Proteins
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Membrane Proteins
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RNA
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Leukotriene D4
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Arachidonate 5-Lipoxygenase
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Matrix Metalloproteinase 2