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* Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129;
Harvard Medical School, Boston, MA 02115;
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129;
Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA 02115; and
¶ Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis at Harvard Medical School, Boston, MA 02115
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institutes of Health (to R.E.G. and A.D.L.), the American Heart Association (Grant-in-Aid to R.E.G.), the Donald W. Reynolds Foundation (to R.E.G. and M.A.), and a predoctoral award from the Sarnoff Cardiovascular Research Foundation (to N.A.).
2 Address correspondence and reprint requests to Dr. Robert E. Gerszten at Cardiology Division and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital East-8307, 149 13th Street, Charlestown, MA 02129. E-mail address: rgerszten{at}partners.org
3 Abbreviations used in this paper: 5-LO, 5-lipoxygenase; LTA4, leukotriene A4; LTB4, leukotriene B4; LTD4, leukotriene D4; AAA, abdominal aortic aneurysm; Ang II, angiotensin II; qPCR, quantitative RT-PCR; MMP, matrix metalloproteinase; SMC, smooth muscle cell.
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