title: Ivabradine reduces chemokine-induced CD4-positive lymphocyte migration.
abstract: OBJECTIVE
  Migration of CD4-positive lymphocytes into the vessel wall is a critical step in atherogenesis. Recent data suggest that ivabradine, a selective I(f)-channel blocker, reduces atherosclerotic plaque formation in apolipoprotein E-deficient mice, hitherto nothing is known about the mechanism by which ivabradine modulates plaque formation. Therefore, the present study investigated whether ivabradine regulates chemokine-induced migration of lymphocytes.
  
  
  RESULTS
  Stimulation of CD4-positive lymphocytes with SDF-1 leads to a 2.0 ± 0.1 fold increase in cell migration (P < .01; n = 7). Pretreatment of cells with ivabradine reduces this effect to a maximal 1.2 ± 0.1 fold induction at 0.1 µmol/L ivabradine (P < .01 compared to SDF-1-treated cells, n = 7). The effect of ivabradine on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity as determined by PI-3 kinase activity assays. Downstream, ivabradine inhibits activation of the small GTPase Rac and phosphorylation of the Myosin Light Chain (MLC). Moreover, ivabradine treatment reduces f-actin formation as well as ICAM3 translocation to the uropod of the cell, thus interfering with two important steps in T cell migration.
  
  
  CONCLUSIONS
  Ivabradine inhibits chemokine-induced migration of CD4-positive lymphocytes. Given the crucial importance of chemokine-induced T-cell migration in early atherogenesis, ivabradine may be a promising tool to modulate this effect.
authors.affiliation: Department of Internal Medicine II-Cardiology, University of Ulm, Robert-Koch-Straresse, 89081 Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walcher
authors.forename: Peter
authors.initials: P
authors.lastname: Bernhardt
authors.forename: Dusica
authors.initials: D
authors.lastname: Vasic
authors.forename: Helga
authors.initials: H
authors.lastname: Bach
authors.forename: Renate
authors.initials: R
authors.lastname: Durst
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rottbauer
authors.forename: Daniel
authors.initials: D
authors.lastname: Walcher
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology; D001552:Benzazepines / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D018946:Chemokine CCL5 / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D018925:Chemokines / Q000276:immunology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D000077550:Ivabradine; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors
chemical_list: D000199:Actins; D015703:Antigens, CD; D001552:Benzazepines; C515255:CXCL12 protein, human; D015815:Cell Adhesion Molecules; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D018925:Chemokines; D004791:Enzyme Inhibitors; C483616:ICAM3 protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077550:Ivabradine; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein