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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2644.)
© 2006 American Heart Association, Inc.

Vascular Biology

Antioxidants Relieve Phosphatase Inhibition and Reduce PDGF Signaling in Cultured VSMCs and in Restenosis

Kai Kappert; Jan Sparwel; Åsa Sandin; Alexander Seiler; Udo Siebolts; Olli Leppänen; Stephan Rosenkranz; Arne Östman

From the Department of Oncology-Pathology (K.K., J.S., Å.S., A.Ö.), Karolinska Institutet, Stockholm, Sweden; Clinic for Internal Medicine III (J.S., S.R.), University of Cologne, Germany; Institute of Clinical Molecular Biology and Tumor Genetics (A.S.), GSF-Research Centre for Environment and Health, Munich, Germany; Institute for Pathology (U.S.), University of Cologne, Germany; Division of Vascular Surgery (O.L.), Uppsala University Hospital, Uppsala, Sweden; and the Center for Molecular Medicine Cologne (CMMC) (S.R.), University of Cologne, Germany.

Correspondence to Arne Östman, Department of Oncology-Pathology, Karolinska Institutet, 17176 Stockholm, Sweden. E-mail arne.ostman{at}ki.se

Objective— Growth factor– and reactive oxygen species (ROS)-induced activation of VSMCs is involved in vascular disease. This study investigates whether inhibitory oxidation of protein tyrosine phosphatases (PTPs) contributes to signaling in VSMCs in vitro and in vivo, and analyzes whether ROS- and growth factor–dependent vascular smooth muscle cell (VSMC) signaling is blunted by antioxidants that are able to activate oxidized PTPs.

Methods and Results— Signaling induced by H₂O₂ and platelet-derived growth factor (PDGF) was analyzed in VSMCs with or without the antioxidants N-acetyl-cysteine (NAC) and tempol. Effects of antioxidants on PDGF-stimulated chemotaxis and proliferation were determined. In vivo effects of antioxidants were analyzed in the rat carotid balloon-injury model, by analyzing neointima formation, cell proliferation, PDGF ß-receptor status, and PTP expression and activity. NAC treatment prevented H₂O₂-induced PTP inhibition, and reduced H₂O₂- and ligand-induced PDGF ß-receptor phosphorylation, PDGF-induced proliferation, and chemotaxis of VSMCs. Antioxidants inhibited neointima formation and reduced PDGF receptor phosphorylation in the neointima and also increased PTP activity.

Conclusion— PTP-inhibition was identified as an intrinsic component of H₂O₂- and PDGF-induced signaling in cultured VSMCs. The reduction in PDGF ß-receptor phosphorylation in vivo, and the increase in PTP activity, by antioxidants indicate activation of oxidized PTPs as a previously unrecognized mechanism for the antirestenotic effects of antioxidants. The findings thus suggest, in general terms, reactivation of oxidized PTPs as a novel antirestenotic strategy.

Growth factor– and reactive oxygen species–induced activation of VSMCs is involved in vascular disease. This study demonstrates that inhibitory oxidation of protein tyrosine phosphatases (PTPs) contributes to signaling in VSMCs in vitro and in vivo, and that antioxidants can effectively reactivate oxidized PTPs and thereby reduce PDGF signaling and neointima formation.

Key Words: restenosis • VSMC • protein tyrosine phosphatase • platelet-derived growth factor • neointima formation

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