Pharmacological inhibition of BLT1 diminishes early abdominal aneurysm formation.
Leukotriene B(4) (LTB(4)) is a pro-inflammatory lipid mediator generated by the enzymes 5-lipoxygenase (5-LO) and LTA(4)-hydrolase. LTB(4) signals primarily through its 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. Here we tested the hypothesis that pharmacological inhibition of BLT1 diminishes abdominal aortic aneurysm (AAA) formation, a major complication associated with atherosclerotic vascular disease. Chow-fed Apoe(-/-) mice were treated with a 4-week infusion of Angiotensin II (AngII, 1000 ng/(kg min)) beginning at 10 weeks of age, in a well-established murine AAA model. Administration of the selective BLT1 antagonist CP-105,696 beginning simultaneously with AngII infusion reduced the incidence of AAA formation from 82% to 40% (p<0.05). There was a concordant reduction in maximal aortic diameter from 2.35 mm to 1.56 mm (p<0.05). While administration of the antagonist on day 14 after the onset of AngII infusion diminished lesional macrophage accumulation, it did not significantly alter the size of AAA by day 42. Thus, pharmacological inhibition of BLT1 may ultimately hold clinical promise, but early intervention may be critical.
Kristo
Fjoralba
F
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129, United States.
Hardy
Gregory J
GJ
Anderson
Thomas J T
TJ
Sinha
Sumita
S
Ahluwalia
Neil
N
Lin
Alexander Y
AY
Passeri
Jonathan
J
Scherrer-Crosbie
Marielle
M
Gerszten
Robert E
RE
D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001011:Aorta / Q000000981:diagnostic imaging; D017544:Aortic Aneurysm, Abdominal / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control*; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D002633:Chemotaxis; D018450:Disease Progression; D007150:Immunohistochemistry; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D014463:Ultrasonography
D001578:Benzopyrans; D002264:Carboxylic Acids; D000804:Angiotensin II; D007975:Leukotriene B4; C089698:CP 105696