Leukotriene B4 receptor antagonism reduces monocytic foam cells in mice.
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.
Aiello
Robert J
RJ
Department of Cardiovascular and Metabolic Disease, Pfizer Global Research and Development, Groton, Conn 06340, USA. robert_j_aiello@groton.pfizer.com.
Bourassa
Patricia-Ann
PA
Lindsey
Saralyn
S
Weng
Weifan
W
Freeman
Ann
A
Showell
Henry J
HJ
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D001578:Benzopyrans / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000235:genetics; D018450:Disease Progression; D005487:Foam Cells; D007150:Immunohistochemistry; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000502:physiology; D008055:Lipids / Q000097:blood; D016177:Macrophage-1 Antigen / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*
D001057:Apolipoproteins E; D001578:Benzopyrans; D002264:Carboxylic Acids; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D020024:Leukotriene Antagonists; D008055:Lipids; D016177:Macrophage-1 Antigen; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D011973:Receptors, LDL; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; C089698:CP 105696