leukotriene-d4 and Hyperlipidemias

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.

Topics: 5-Lipoxygenase-Activating Proteins; Analysis of Variance; Animals; Aortic Aneurysm, Abdominal; Arachidonate 5-Lipoxygenase; Blotting, Western; Carrier Proteins; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Chemokine CXCL1; Chemokines, CXC; Cholates; Connective Tissue; Cytokines; Diet, Atherogenic; DNA Primers; Gene Expression Regulation; Histological Techniques; Humans; Hyperlipidemias; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Leukotriene D4; Leukotrienes; Macrophage Inflammatory Proteins; Macrophages; Matrix Metalloproteinase 2; Membrane Proteins; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Reverse Transcriptase Polymerase Chain Reaction; RNA