title: Differential leukotriene receptor expression and calcium responses in endothelial cells and macrophages indicate 5-lipoxygenase-dependent circuits of inflammation and atherogenesis.
abstract: OBJECTIVE
  Inflammatory infiltrates and atherosclerotic lesions emerge when monocytes adhere to endothelial cells (ECs), migrate into the subendothelial space, and become macrophages (MPhi(s)). Leukotrienes (LTs), products of 5-lipoxygenase, are powerful inflammatory mediators. 5-lipoxygenase+ MPhi(s) have been shown to increase during atherogenesis, and LT receptor (LT-R) transcripts were identified in diseased arteries. To investigate LT-Rs in cells involved in inflammation and atherogenesis, we used the in vitro models of human umbilical vein ECs (HUVECs) and monocyte-derived MPhi(s).
  
  
  RESULTS
  HUVECs primarily expressed transcripts of the cysteinyl (cys) LT2-R, which was strongly upregulated by interleukin-4. By contrast, MPhi(s) predominantly expressed transcripts of the cysLT1-R. Calcium responses toward LTs revealed differential cysLT-R utilization by both cell types: HUVECs responded to both cysLTs, whereas MPhi(s) preferentially responded to LTD4; HUVECs, but not MPhi(s), were resistant toward a cysLT1-R antagonist, montelukast; cysLTs generated regular calcium oscillations in HUVECs that lasted >60 minutes, resulting in >500 oscillations per cell. By contrast, calcium elevations in MPhi(s) returned to baseline within seconds and were nonoscillatory.
  
  
  CONCLUSIONS
  Our data raise the possibility that MPhi-derived LTs differentially activate cysLT2-Rs via paracrine stimulation and cysLT1-Rs via autocrine and paracrine stimulation during inflammation and atherogenesis.
authors.affiliation: Institute for Vascular Medicine, Friedrich-Schiller-University of Jena, Erfurt, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Lötzer
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanbroek
authors.forename: Markus
authors.initials: M
authors.lastname: Hildner
authors.forename: Anja
authors.initials: A
authors.lastname: Urbach
authors.forename: Regine
authors.initials: R
authors.lastname: Heller
authors.forename: Ellen
authors.initials: E
authors.lastname: Bretschneider
authors.forename: Helen
authors.initials: H
authors.lastname: Galczenski
authors.forename: Jilly F
authors.initials: JF
authors.lastname: Evans
authors.forename: Andreas J R
authors.initials: AJ
authors.lastname: Habenicht
mesh_terms: D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism*; D018077:Receptors, Leukotriene / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018077:Receptors, Leukotriene; D001094:Arachidonate 5-Lipoxygenase; D002118:Calcium