Inhibited aortic aneurysm formation in BLT1-deficient mice.
Leukotriene B(4) is a proinflammatory lipid mediator generated by the enzymes 5-lipoxygenase and leukotriene A(4) hydrolase. Leukotriene B(4) signals primarily through its high-affinity G protein-coupled receptor, BLT1, which is highly expressed on specific leukocyte subsets. Recent genetic studies in humans as well as knockout studies in mice have implicated the leukotriene synthesis pathway in several vascular pathologies. In this study, we tested the hypothesis that BLT1 is necessary for abdominal aortic aneurysm (AAA) formation, a major complication of atherosclerotic vascular disease. Chow-fed Apoe(-/-) and Apoe(-/-)/Blt1(-/-) mice were treated with a 4-wk infusion of angiotensin II (1000 ng/min/kg) beginning at 20 wk of age, in a well-established murine AAA model. We found a reduced incidence of AAA formation as well as concordant reductions in the maximum suprarenal/infrarenal diameter and total suprarenal/infrarenal area in the angiotensin II-treated Apoe(-/-)/Blt1(-/-) mice as compared with the Apoe(-/-) controls. Diminished AAA formation in BLT1-deficient mice was associated with significant reductions in mononuclear cell chemoattractants and leukocyte accumulation in the vessel wall, as well as striking reductions in the production of matrix metalloproteinases-2 and -9. Thus, we have shown that BLT1 contributes to the frequency and size of abdominal aortic aneurysms in mice and that BLT1 deletion in turn inhibits proinflammatory circuits and enzymes that modulate vessel wall integrity. These findings extend the role of BLT1 to a critical complication of vascular disease and underscore its potential as a target for intervention in modulating multiple pathologies related to atherosclerosis.
Ahluwalia
Neil
N
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Lin
Alexander Y
AY
Tager
Andrew M
AM
Pruitt
Ivy E
IE
Anderson
Thomas J T
TJ
Kristo
Fjoralba
F
Shen
Dongxiao
D
Cruz
Anna R
AR
Aikawa
Masanori
M
Luster
Andrew D
AD
Gerszten
Robert E
RE
D000818:Animals; D001012:Aorta, Abdominal / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002464:Cell Migration Inhibition; D004195:Disease Models, Animal; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018102:Receptors, Leukotriene B4 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D001057:Apolipoproteins E; C503704:Ltb4r1 protein, mouse; D061965:Matrix Metalloproteinase Inhibitors; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse