title: Role of leukotriene B4 receptors in the development of atherosclerosis: potential mechanisms.
abstract: 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.
  
  
  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.
authors.affiliation: James Graham Brown Cancer Center, University of Louisville Health Sciences, Louisville, KY 40202, USA.
authors.forename: Krishnaprasad
authors.initials: K
authors.lastname: Subbarao
authors.forename: Venkatakrishna R
authors.initials: VR
authors.lastname: Jala
authors.forename: Steven
authors.initials: S
authors.lastname: Mathis
authors.forename: Jill
authors.initials: J
authors.lastname: Suttles
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Zacharias
authors.forename: Jasimuddin
authors.initials: J
authors.lastname: Ahamed
authors.forename: Hydar
authors.initials: H
authors.lastname: Ali
authors.forename: Michael T
authors.initials: MT
authors.lastname: Tseng
authors.forename: Bodduluri
authors.initials: B
authors.lastname: Haribabu
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000502:physiology; D001161:Arteriosclerosis / Q000209:etiology* / Q000235:genetics; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology; D003433:Crosses, Genetic; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007975:Leukotriene B4 / Q000502:physiology; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018077:Receptors, Leukotriene / Q000096:biosynthesis / Q000502:physiology; D018102:Receptors, Leukotriene B4 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; D012333:RNA, Messenger; D018077:Receptors, Leukotriene; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; C412377:leukotriene B2 receptor