Inhibited Aortic Aneurysm Formation in BLT1-Deficient Mice

Abstract

Leukotriene B4 is a proinflammatory lipid mediator generated by the enzymes 5-lipoxygenase and leukotriene A4 hydrolase. Leukotriene B4 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.

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…Apolipoprotein E and BLT 1 R double knockout mice display smaller lesions compared with their apoE(Ϫ/Ϫ) littermates Heller et al, 2005;Bä ck, 2008b). The latter double knockout mice are also protected from abdominal aortic aneurysm development induced by angiotensin II infusion (Ahluwalia et al, 2007).…”

“…The importance of BLT 1 R signaling has also received support from animal studies. Either genetic or pharmacological targeting of BLT 1 R signaling reduces the incidence of experimental abdominal aortic aneurysms induced by angiotensin infusion in apoE knockout mice (Ahluwalia et al, 2007;Kristo et al, 2010).…”

Leukotriene B4 Augments and Restores FcγRs-dependent Phagocytosis in Macrophages

“…The results of several recent studies suggested the importance of BLT1 in atherosclerosis. BLT1 deficiency resulted in reduced atherogenesis in an apoE-deficient background (16), and this effect was explained by reduced level of production of monocyte chemoattractant protein-1 (MCP-1) in BLT1-deficient macrophages (47). Future studies investigating the possible role of LTB 4 -BLT1 signaling, especially Rac activation, in MCP-1 production in macrophages would be of particular interest.…”

Leukotriene B4 Release from Mast Cells in IgE-Mediated Airway Hyperresponsiveness and Inflammation

“…The ability of LTB4 to affect such a wide range of cell types indicates that LTB4 may function broadly in the regulation of innate and adaptive immune responses. LTB4 is essential in host defense against bacterial infection (40), and is linked to many inflammatory disorders, including arthritis (41)(42)(43), atherogenesis (44), and aortic aneurysm formation (45). In animal models and in patients with asthma, the levels of LTB4 have been reported to be elevated in the airways and to correlate with asthma severity (15,16,38,46).…”