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(Circulation. 2005;112:578-586.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Inhibition of Atherogenesis in BLT1-Deficient Mice Reveals a Role for LTB4 and BLT1 in Smooth Muscle Cell Recruitment

Eric A. Heller, MD; Emerson Liu, MD; Andrew M. Tager, MD; Sumita Sinha, PhD; Jesse D. Roberts, MD; Stephanie L. Koehn; Peter Libby, MD; Elena Rabkin Aikawa, MD, PhD; Ji Qiu Chen, MD; Paul Huang, MD; Mason W. Freeman, MD; Kathryn J. Moore, PhD; Andrew D. Luster, MD, PhD; Robert E. Gerszten, MD

From the Center for Immunology and Inflammatory Diseases (E.A.H., E.L., A.M.T., S.S., A.D.L., R.E.G.), Cardiovascular Research Center (E.A.H., E.L., J.D.R., J.Q.C., P.H., R.E.G.), Massachusetts General Hospital, Charlestown, and Harvard Medical School, Boston, Mass; Lipid Metabolism Unit and Endocrine Division (S.L.K., M.W.F., K.J.M.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Vascular Medicine and Atherosclerosis Unit (P.L., E.R.A.), Cardiovascular Division, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Mass; and Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis at Harvard Medical School (P.L., E.R.A., R.E.G.), Boston, Mass.

Correspondence to Dr R.E. Gerszten, Cardiology Division and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital East-8307, 149 13th St, Charlestown, MA 02129. E-mail rgerszten{at}partners.org

Received March 2, 2005; revision received April 7, 2005; accepted April 12, 2005.

Background— It is known that 5-lipoxygenase and its product, leukotriene B4 (LTB₄), are highly expressed in several human pathologies, including atherosclerotic plaque. LTB₄ signals primarily through its high-affinity G protein-coupled receptor BLT1, which is expressed on specific leukocyte subsets. BLT1 receptor expression and function on other atheroma-associated cell types is unknown.

Methods and Results— To directly assess the role of the LTB₄-BLT1 pathway in atherogenesis, we bred BLT1^–/– mice into the atherosclerosis-susceptible apoE^–/– strain. Compound-deficient apoE^–/–/Blt1^–/– mice fed a Western-type diet had a marked reduction in plaque formation compared with apoE^–/– controls. Immunohistochemical analysis of atherosclerotic lesions in compound-deficient mice revealed a striking decrease in smooth muscle cells (SMCs) and significant decreases in macrophages and T cells. We report here novel evidence of the expression and function of BLT1 on vascular SMCs. LTB₄ triggered SMC chemotaxis, which was pertussis toxin sensitive in Blt1^+/+ SMCs and absent in Blt1^–/– cells, suggesting that BLT1 was the dominant receptor mediating effector functions through a G protein-coupled signaling pathway. Furthermore, BLT1 colocalized with SMCs in human atherosclerotic lesions.

Conclusions— These new findings extend the role of inducible BLT1 to nonleukocyte populations and suggest an important target for intervention to modulate the response to vascular injury.

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