The CX3C chemokine fractalkine induces vascular dysfunction by generation of superoxide anions.
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.
Schäfer
Andreas
A
Medizinische Klinik und Poliklinik I, Universitätsklinikum, Julius-Maximilians-Universität Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. a.schaefer@medizin.uni-wuerzburg.de
Schulz
Christian
C
Fraccarollo
Daniela
D
Tas
Piet
P
Leutke
Meike
M
Eigenthaler
Martin
M
Seidl
Stefan
S
Heider
Peter
P
Ertl
Georg
G
Massberg
Steffen
S
Bauersachs
Johann
J
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
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