HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ahluwalia, N. Articles by Gerszten, R. E. Search for Related Content PubMed PubMed Citation Articles by Ahluwalia, N. Articles by Gerszten, R. E. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Aortic Aneurysm

Inhibited Aortic Aneurysm Formation in BLT1-Deficient Mice¹

Neil Ahluwalia^*,,, Alexander Y. Lin^*,,, Andrew M. Tager^*,, Ivy E. Pruitt^*,, Thomas J. T. Anderson^*,, Fjoralba Kristo^*,, Dongxiao Shen^*,, Anna R. Cruz^*,, Masanori Aikawa^,, Andrew D. Luster^*, and Robert E. Gerszten^2,*,,,¶

^* 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.

This article has been cited by other articles:

				N. Miyahara, H. Ohnishi, S. Miyahara, K. Takeda, S. Matsubara, H. Matsuda, M. Okamoto, J. E. Loader, A. Joetham, M. Tanimoto, et al. Leukotriene B4 Release from Mast Cells in IgE-Mediated Airway Hyperresponsiveness and Inflammation Am. J. Respir. Cell Mol. Biol., June 1, 2009; 40(6): 672 - 682. [Abstract] [Full Text] [PDF]

				X. Houard, V. Ollivier, L. Louedec, J.-B. Michel, and M. Back Differential inflammatory activity across human abdominal aortic aneurysms reveals neutrophil-derived leukotriene B4 as a major chemotactic factor released from the intraluminal thrombus FASEB J, May 1, 2009; 23(5): 1376 - 1383. [Abstract] [Full Text] [PDF]

				L. A. Cassis, M. Gupte, S. Thayer, X. Zhang, R. Charnigo, D. A. Howatt, D. L. Rateri, and A. Daugherty ANG II infusion promotes abdominal aortic aneurysms independent of increased blood pressure in hypercholesterolemic mice Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1660 - H1665. [Abstract] [Full Text] [PDF]

				H. Hlawaty, M.-P. Jacob, L. Louedec, D. Letourneur, C. Brink, J.-B. Michel, L. Feldman, and M. Back Leukotriene Receptor Antagonism and the Prevention of Extracellular Matrix Degradation During Atherosclerosis and In-Stent Stenosis Arterioscler Thromb Vasc Biol, April 1, 2009; 29(4): 518 - 524. [Abstract] [Full Text] [PDF]

				H. Allayee, A. Baylin, J. Hartiala, H. Wijesuriya, M. Mehrabian, A. J Lusis, and H. Campos Nutrigenetic association of the 5-lipoxygenase gene with myocardial infarction Am. J. Clinical Nutrition, October 1, 2008; 88(4): 934 - 940. [Abstract] [Full Text] [PDF]