title: The leukotriene B4 receptor (BLT) antagonist BIIL284 decreases atherosclerosis in ApoE-/- mice.
abstract: Leukotriene B4 (LTB4) induces proinflammatory signaling through BLT receptors expressed in atherosclerotic lesions. Either genetic or pharmacological targeting of the high affinity LTB4 receptor, BLT1, reduces atherosclerosis in different mouse models. The low affinity BLT2 receptor for LTB4 may transduce additional pro-atherogenic signaling, but combined BLT1 and BLT2 receptor antagonism has not previously been explored in atherosclerosis. The aim of the present study was to unravel the effects of the BLT receptor antagonist BIIL284 in apolipoprotein E deficient mice in terms of atherosclerotic lesion size and composition, as well as on arterial matrixmetalloproteinase (MMP) activity and plasma cytokines. Oral administration of BIIL284 (0.3-3mg/kg) dose-dependently decreased atherosclerotic lesion size after 12 weeks. In addition, significantly smaller aortic lesions were observed in mice treated with BIIL284 (3mg/kg) for 24 weeks. The reduced atherosclerosis was associated with less lesion smooth muscle cells, less arterial MMP activities and lower plasma levels of TNF-α and IL-6. Taken together, these results suggest a therapeutic value of BLT receptor antagonism in atherosclerosis.
authors.affiliation: Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, 17176 Stockholm, Sweden.
authors.forename: Daniel F J
authors.initials: DF
authors.lastname: Ketelhuth
authors.affiliation: Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, 17176 Stockholm, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hermansson
authors.affiliation: INSERM U1148 (ex U698), Bichat Hospital, 75018 Paris, France.
authors.forename: Hanna
authors.initials: H
authors.lastname: Hlawaty
authors.affiliation: INSERM U1148 (ex U698), Bichat Hospital, 75018 Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Letourneur
authors.affiliation: Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, 17176 Stockholm, Sweden.
authors.forename: Zhong-qun
authors.initials: ZQ
authors.lastname: Yan
authors.affiliation: Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Cardiology, Karolinska University Hospital, 17176 Stockholm, Sweden. Electronic address: Magnus.Back@ki.se.
authors.forename: Magnus
authors.initials: M
authors.lastname: Bäck
mesh_terms: D000578:Amidines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002219:Carbamates / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics
chemical_list: D000578:Amidines; D001057:Apolipoproteins E; D002219:Carbamates; D016207:Cytokines; D012333:RNA, Messenger; D018102:Receptors, Leukotriene B4; D019714:Tissue Inhibitor of Metalloproteinases; C424425:amelubant; D020782:Matrix Metalloproteinases
keywords: Atherosclerosis; Inflammation; Leukotriene receptor; Lipoxygenase