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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:369.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Role of Leukotriene B₄ Receptors in the Development of Atherosclerosis: Potential Mechanisms

Krishnaprasad Subbarao; Venkatakrishna R. Jala; Steven Mathis; Jill Suttles; Wolfgang Zacharias; Jasimuddin Ahamed; Hydar Ali; Michael T. Tseng; Bodduluri Haribabu

From the James Graham Brown Cancer Center (K.S., V.R.J., B.H.) and the Departments of Microbiology and Immunology (S.M., J.S., B.H.), Medicine and Pharmacology & Toxicology (W.Z.), Anatomical Sciences & Neurobiology (M.T.T.), University of Louisville Health Sciences, Louisville, KY; and Department of Pathology (J.A., H.A.), University of Pennsylvania, School of Dental Medicine, Philadelphia, PA.

Correspondence to Dr Bodduluri Haribabu, Delia Baxter Bldg, University of Louisville, 580 South Preston Street, #119B, Louisville, KY 40202. E-mail H0bodd01{at}gwise.louisville.edu

Objective— Leukotriene B₄ (LTB₄), a potent leukocyte chemoattractant, is known to promote several inflammatory diseases, including atherosclerosis. We sought to determine mechanisms through which LTB₄ modulates atherosclerosis in cell lines expressing LTB₄ receptors, BLT-1, and in mice deficient in BLT-1 as well as macrophage cell lines derived from BLT-1^+/+ and BLT-1^-/- mice.

Methods and Results— Analysis of global changes in gene expression induced by LTB₄ in rat basophilic leukemia cells (RBL-2H3) expressing the human BLT-1 showed highest-fold increase in expression of fatty acid translocase/CD36 and the chemokine MCP1/JE/CCL2 , which are critical in atherogenesis. To determine the importance of BLT-1 in atherogenesis, we crossed BLT-1-null mice with apolipoprotein (apo)-E-deficient mice, which develop severe atherosclerosis. Deletion of BLT-1 significantly reduced the lesion formation in apo-E^-/- mice only during initiating stages (4 and 8 weeks) but had no effect on the lesion size in mice fed atherogenic diet for 19 weeks. Macrophage cell lines from BLT-1-deficient mice expressed the low-affinity LTB₄ receptor, BLT-2, and exhibited chemotaxis to LTB₄.

Conclusions— The effects of LTB₄ in atherosclerosis are likely mediated through the high-affinity BLT-1 and the low-affinity BLT-2 receptors. LTB₄ promotes atherosclerosis by chemo-attracting monocytes, by providing an amplification loop of monocyte chemotaxis via CCL2 production, and by converting monocytes to foam cells by enhanced expression of CD36 and fatty acid accumulation.

Key Words: atherosclerosis • monocyte/macrophages • leukotriene B₄ receptors

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