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.
Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.
Lei
L
Zhao
Michael P W
MP
Moos
Rolf
R
Gräbner
Frédérique
F
Pédrono
Jinjin
J
Fan
Brigitte
B
Kaiser
Nicole
N
John
Sandra
S
Schmidt
Rainer
R
Spanbroek
Katharina
K
Lötzer
Li
L
Huang
Jisong
J
Cui
Daniel J
DJ
Rader
Jilly F
JF
Evans
Andreas J R
AJ
Habenicht
Colin D
CD
Funk
D058927:5-Lipoxygenase-Activating Proteins; D000704:Analysis of Variance; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D018932:Chemokine CCL2 / Q000097:blood; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000378:metabolism; D020355:Cholates; D003238:Connective Tissue / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D017931:DNA Primers; D004036:Diet, Atherogenic; D005786:Gene Expression Regulation; D006652:Histological Techniques; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications*; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D017998:Leukotriene D4 / Q000378:metabolism; D015289:Leukotrienes / Q000096:biosynthesis*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000378:metabolism; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; C548593:Alox5ap protein, mouse; C111835:CCL2 protein, human; C475829:CXCL1 protein, human; D002352:Carrier Proteins; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D020355:Cholates; D016207:Cytokines; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D015289:Leukotrienes; D019402:Macrophage Inflammatory Proteins; D008565:Membrane Proteins; D012313:RNA; D017998:Leukotriene D4; D001094:Arachidonate 5-Lipoxygenase; D020778:Matrix Metalloproteinase 2