Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:443-449
doi: 10.1161/hq0302.105593
doi: 10.1161/hq0302.105593
© 2002 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Leukotriene B4 Receptor Antagonism Reduces Monocytic Foam Cells in Mice
From the Departments of Cardiovascular and Metabolic Disease (R.J.A., P.-A.B., S.L., W.W., A.F.) and Inflammation (H.J.S.), Pfizer Global Research and Development, Groton, Conn.
Address correspondence to Dr. Robert J. Aiello, Pfizer Inc, PGRD, Eastern Point Rd, Groton, CT 06340. E-mail robert_j_aiello{at}groton.pfizer.com
Leukotriene B4 (LTB4) is a potent chemotactic agent that activates monocytes through the LTB4 receptor (BLTR). We tested the hypothesis that LTB4 receptor blockade would slow atherosclerotic progression by inhibiting monocyte recruitment. Homozygous low-density receptor knockout (LDLr-/-) mice and apolipoprotein E deficient (apoE-/-) mice were treated with a specific LTB4 receptor antagonist, CP-105,696, for 35 days. In apoE-/-mice, treatment with the LTB4 antagonist did not affect plasma lipid concentrations but significantly reduced CD11b levels both in vascular lesions and whole blood. Compared with age-matched controls, lipid accumulation and monocyte infiltration were significantly reduced in treated apoE-/- mice at all time points tested. Lesion area reduction was also demonstrated in LDLr-/- mice maintained on a high-fat diet. LTB4 antagonism had no significant effect on lesion size in mice possessing the null alleles for another chemotactic agent, monocyte chemoattractant protein-1 (MCP-1-/-xapoE-/-), suggesting MCP-1 and LTB4 may either interact or exert their effects by a common mechanism. These results demonstrate that in a preclinical model of atherosclerosis LTB4 receptor blockade reduces lesion progression and further suggest a previously unrecognized role for LTB4 or other oxidized lipids recognized by the BLTR receptor in the pathogenesis of this disease.
Key Words: leukotriene B4 • atherosclerosis • monocyte chemoattractant protein-1
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