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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:55.)
© 2007 American Heart Association, Inc.

Vascular Biology

The CX₃C Chemokine Fractalkine Induces Vascular Dysfunction by Generation of Superoxide Anions

Andreas Schäfer; Christian Schulz; Daniela Fraccarollo; Piet Tas; Meike Leutke; Martin Eigenthaler; Stefan Seidl; Peter Heider; Georg Ertl; Steffen Massberg; Johann Bauersachs

From Medizinische Klinik und Poliklinik I (A.S., D.F., M.L., G.E., J.B.), Universitätsklinikum, Julius-Maximilians-Universität Würzburg, Germany; Deutsches Herzzentrum und 1. Medizinische Klinik (C.S., S.M.), Technische Universität München, Germany; Klinik und Poliklinik für Anästhesiologie (P.T.), Universitätsklinikum, Julius-Maximilians-Universität Würzburg, Germany; Institut für Klinische Biochemie und Pathobiochemie (M.E.), Julius-Maximilians-Universität Würzburg, Germany; Institut für Pathologie (S.S.), Klinikum rechts der Isar, Technische Universität München, Germany; Abteilung Gefässchirurgie (P.H.), Klinikum rechts der Isar, Technische Universität München, Germany.

Correspondence to Andreas Schäfer, Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. E-mail a.schaefer{at}medizin.uni-wuerzburg.de

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.

Methods and 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 µg/mL) did not directly induce contractile or relaxant responses when applied to rat aortic rings in organ baths. Short-term incubation with fractalkine (1 µg/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.

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.

We investigated direct effects of fractalkine on vascular function. We demonstrate increased superoxide formation and decreased nitric oxide bioavailability in rat aorta by fractalkine. Induction of vascular dysfunction could provide an alternate mechanism by which fractalkine exerts its pro-atherosclerotic effects.

Key Words: chemokines • endothelial dysfunction • nitric oxide • reactive oxygen species

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