title: Myeloid cell 5-lipoxygenase activating protein modulates the response to vascular injury.
abstract: Human genetics have implicated the 5-lipoxygenase enzyme in the pathogenesis of cardiovascular disease, and an inhibitor of the 5-lipoxygenase activating protein (FLAP) is in clinical development for asthma.
  
  
  
  Here we determined whether FLAP deletion modifies the response to vascular injury.
  
  
  
  Vascular remodeling was characterized 4 weeks after femoral arterial injury in FLAP knockout mice and wild-type controls. Both neointimal hyperplasia and the intima/media ratio of the injured artery were significantly reduced in the FLAP knockouts, whereas endothelial integrity was preserved. Lesional myeloid cells were depleted and vascular smooth muscle cell (VSMC) proliferation, as reflected by bromodeoxyuridine incorporation, was markedly attenuated by FLAP deletion. Inflammatory cytokine release from FLAP knockout macrophages was depressed, and their restricted ability to induce VSMC migration ex vivo was rescued with leukotriene B(4). FLAP deletion restrained injury and attenuated upregulation of the extracellular matrix protein, tenascin C, which affords a scaffold for VSMC migration. Correspondingly, the phenotypic modulation of VSMC to a more synthetic phenotype, reflected by morphological change, loss of α-smooth muscle cell actin, and upregulation of vascular cell adhesion molecule-1 was also suppressed in FLAP knockout mice. Transplantation of FLAP-replete myeloid cells rescued the proliferative response to vascular injury.
  
  
  
  Expression of lesional FLAP in myeloid cells promotes leukotriene B(4)-dependent VSMC phenotypic modulation, intimal migration, and proliferation.
authors.affiliation: The Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104-5158, USA.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Yu
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ricciotti
authors.forename: Takashi
authors.initials: T
authors.lastname: Miwa
authors.forename: Shulin
authors.initials: S
authors.lastname: Liu
authors.forename: Kaori
authors.initials: K
authors.lastname: Ihida-Stansbury
authors.forename: Gavin
authors.initials: G
authors.lastname: Landesberg
authors.forename: Peter L
authors.initials: PL
authors.lastname: Jones
authors.forename: Rosario
authors.initials: R
authors.lastname: Scalia
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Song
authors.forename: Richard K
authors.initials: RK
authors.lastname: Assoian
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003545:Cysteine / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005263:Femoral Artery / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D005838:Genotype; D006965:Hyperplasia; D018836:Inflammation Mediators / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D015289:Leukotrienes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000276:immunology / Q000293:injuries / Q000473:pathology; D022423:Myeloid Cells / Q000201:enzymology* / Q000276:immunology / Q000637:transplantation; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D058426:Neointima; D010641:Phenotype; D019063:Tenascin / Q000378:metabolism; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D057772:Vascular System Injuries / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548593:Alox5ap protein, mouse; D018836:Inflammation Mediators; D015289:Leukotrienes; D019063:Tenascin; D019010:Vascular Cell Adhesion Molecule-1; C112381:cysteinyl-leukotriene; D007975:Leukotriene B4; D003545:Cysteine