title: The CX3C chemokine fractalkine induces vascular dysfunction by generation of superoxide anions.
abstract: OBJECTIVE
  The chemokine fractalkine activates platelets and induces leukocyte adhesion to the endothelium. Expression of fractalkine and its receptor, CX3CR1, is elevated in coronary artery disease. We assessed the effects of fractalkine on vascular function in isolated rat aorta.
  
  
  RESULTS
  CX3CR1 expression was demonstrated in rat aortic endothelial and smooth muscle cells by immunohistochemistry, Western blot, and polymerase chain reaction (PCR). Fractalkine (up to 1 microg/mL) did not directly induce contractile or relaxant responses when applied to rat aortic rings in organ baths. Short-term incubation with fractalkine (1 microg/mL) for 5 minutes did not affect vascular reactivity. Pretreatment of isolated rat aortic rings with fractalkine for 2 hours impaired acetylcholine-induced nitric oxide (NO)-mediated relaxation after preconstriction with phenylephrine in a concentration-dependent manner. The concentration response to the NO donor DEA-NONOate was significantly shifted to the right. The radical scavenger tiron normalized the attenuated acetylcholine-induced relaxation after fractalkine incubation. Aortic superoxide formation was enhanced by fractalkine, which was inhibited by diphenyleneiodonium but not by inhibitors of xanthine oxidase or NO synthase.
  
  
  CONCLUSIONS
  In addition to its role as a chemokine and adhesion molecule, fractalkine induces vascular dysfunction by stimulating vascular reactive oxygen species resulting in reduced NO bioavailability.
authors.affiliation: Medizinische Klinik und Poliklinik I, Universitätsklinikum, Julius-Maximilians-Universität Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. a.schaefer@medizin.uni-wuerzburg.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäfer
authors.forename: Christian
authors.initials: C
authors.lastname: Schulz
authors.forename: Daniela
authors.initials: D
authors.lastname: Fraccarollo
authors.forename: Piet
authors.initials: P
authors.lastname: Tas
authors.forename: Meike
authors.initials: M
authors.lastname: Leutke
authors.forename: Martin
authors.initials: M
authors.lastname: Eigenthaler
authors.forename: Stefan
authors.initials: S
authors.lastname: Seidl
authors.forename: Peter
authors.initials: P
authors.lastname: Heider
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002478:Cells, Cultured; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000503:physiopathology*; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; C516305:CX3CR1 protein, rat; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; C515540:Cx3cl1 protein, rat; D008565:Membrane Proteins; D019707:Receptors, Chemokine; D014665:Vasodilator Agents; D013481:Superoxides; D009569:Nitric Oxide; D019255:NADPH Oxidases; D000109:Acetylcholine