O208	Fractalkine induces vascular dysfunction and reduces nitric oxide bioavailability by NADHP oxidase activation and increased generation of superoxide anions.
1A.Schäfer, 2Chr.Schulz, 1D.Fraccarollo, 3P.Tas, 1G.Ertl, 1J.Bauersachs
1Medizinische Klinik und Poliklinik I, University of Würzburg, Würzburg, DE; 2Deutsches Herzzentrum München, TU München, München, DE; 3Klinik für Anästhesiologie, University of Würzburg, Würzburg, DE.

Background: Fractalkine activates platelets, induces leukocyte adhesion to the endothelium and facilitates atherosclerosis. The fractalkine receptor has been described on activated endothelial and smooth muscle cells. We assessed whether fractalkine would induce vascular dysfunction. Methods and Results: Incubation of isolated rat aortic rings with fractalkine for 2 hours impaired acetylcholine-induced, nitric oxide (NO)-mediated relaxation (maximum relaxation: control 86±3%, fractalkine 40±4%, p<0.001) after preconstriction with phenylephrine. Inhibition of the chemokine domain of fractalkine by a neutralizing antibody or blocking of fractalkine receptor in vascular tissues by an inhibiting antibody abrogated the effects of fractalkine on acetylcholine-induced relaxation. Furthermore, treatment with the radical scavenger tiron normalized acetylcholine-induced relaxation. Aortic rings which were slightly preconstricted to 15-20% of their maximum contraction displayed less vasoconstriction following NO synthase inhibition with NG-nitro-L-arginine (L-NNA, 100 µmol/L; final contraction in % of maximum: control 91±2, fractalkine 71±8, p<0.05) indicating less basal NO bioavailability after incubation with fractalkine. Fractalkine stimulated aortic (lucigenin [5 µM]-enhanced chemiluminescence) superoxide formation ([arbitrary units] control 1264±110, fractalkine 3697±257, p<0.01), which was normalized by tiron. Superoxide formation detected by ethidiumbromide staining was prominent throughout all layers of the vascular wall. Expression of NADPH oxidase subunit p47 was increased while thioredoxin expression, an endogenous inhibitor of NADPH oxidase, was reduced after incubation with fractalkine. Conclusion: 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.

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