title: Fibrinogen decreases cardiomyocyte contractility through an ICAM-1-dependent mechanism.
abstract: BACKGROUND
  Cardiomyocytes exposed to inflammatory processes express intracellular adhesion molecule-1 (ICAM-1). We investigated whether fibrinogen and fibrinogen degradation products, including D-dimer, could alter cardiomyocyte contractile function through interaction with ICAM-1 found on inflamed cardiomyocytes.
  
  
  METHODS
  In vivo, rats were injected with endotoxin to model systemic inflammation, whereas isolated rat cardiomyocytes were treated with tumor necrosis factor-alpha to model the inflammatory environment seen following exposure to bacterial products such as lipopolysaccharide.
  
  
  RESULTS
  In vivo, endotoxin administration profoundly decreased cardiac contractile function associated with a large increase in intracardiac ICAM-1 and perivascular fibrinogen. Confocal microscopy with double-staining of isolated rat cardiomyocytes demonstrated colocalization of ICAM-1 and fibrinogen. This interaction was disrupted through pre-treatment of the cells with an ICAM-1-blocking antibody. Functionally, isolated rat cardiomyocyte preparations exhibited decreased fractional shortening when incubated with fibrinogen, and through the use of synthetic peptides, we determined that residues 117-133 of the fibrinogen gamma chain are responsible for this interaction with ICAM-1. Despite having crosslinked gamma chains, D-dimer retained the ability to decrease cardiomyocyte contractility.
  
  
  CONCLUSIONS
  Site 117-133 of the fibrinogen gamma chain is able to depress cardiomyocyte contractility through binding ICAM-1.
authors.affiliation: University of British Columbia Critical Care Research Laboratories, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada. jboyd@mrl.ubc.ca
authors.forename: John H
authors.initials: JH
authors.lastname: Boyd
authors.forename: Edmond H
authors.initials: EH
authors.lastname: Chau
authors.forename: Chiho
authors.initials: C
authors.lastname: Tokunanga
authors.forename: Ryon M
authors.initials: RM
authors.lastname: Bateman
authors.forename: Greg
authors.initials: G
authors.lastname: Haljan
authors.forename: Ehsan Y
authors.initials: EY
authors.lastname: Davani
authors.forename: Yinjin
authors.initials: Y
authors.lastname: Wang
authors.forename: Keith R
authors.initials: KR
authors.lastname: Walley
mesh_terms: D000818:Animals; D004731:Endotoxins / Q000494:pharmacology*; D005340:Fibrinogen / Q000378:metabolism / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism* / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D018799:Intercellular Adhesion Molecule-1; D005340:Fibrinogen