This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 26/12/2644    most recent 01.ATV.0000246777.30819.85v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kappert, K. Articles by Östman, A. Search for Related Content PubMed PubMed Citation Articles by Kappert, K. Articles by Östman, A. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB ACETYLCYSTEINE HYDROGEN PEROXIDE Medline Plus Health Information Antioxidants Related Collections Restenosis Animal models of human disease Calcium cycling/excitation-contraction coupling Growth factors/cytokines Oxidant stress Mechanism of atherosclerosis/growth factors

(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

This article has been cited by other articles:

				M. Y. Lee, A. S. Martin, P. K. Mehta, A. E. Dikalova, A. M. Garrido, S. R. Datla, E. Lyons, K.-H. Krause, B. Banfi, J. D. Lambeth, et al. Mechanisms of Vascular Smooth Muscle NADPH Oxidase 1 (Nox1) Contribution to Injury-Induced Neointimal Formation Arterioscler Thromb Vasc Biol, April 1, 2009; 29(4): 480 - 487. [Abstract] [Full Text] [PDF]

				A. Qu, C. Jiang, M. Xu, Y. Zhang, Y. Zhu, Q. Xu, C. Zhang, and X. Wang PGC-1{alpha} attenuates neointimal formation via inhibition of vascular smooth muscle cell migration in the injured rat carotid artery Am J Physiol Cell Physiol, January 1, 2009; 297(3): C645 - C653. [Abstract] [Full Text] [PDF]

				J. Li, X.-L. Niu, and N. R. Madamanchi Leukocyte Antigen-related Protein Tyrosine Phosphatase Negatively Regulates Hydrogen Peroxide-induced Vascular Smooth Muscle Cell Apoptosis J. Biol. Chem., December 5, 2008; 283(49): 34260 - 34272. [Abstract] [Full Text] [PDF]

				M. Zemskova, E. Sahakian, S. Bashkirova, and M. Lilly The PIM1 Kinase Is a Critical Component of a Survival Pathway Activated by Docetaxel and Promotes Survival of Docetaxel-treated Prostate Cancer Cells J. Biol. Chem., July 25, 2008; 283(30): 20635 - 20644. [Abstract] [Full Text] [PDF]

				F. Tabet, E. L. Schiffrin, G. E. Callera, Y. He, G. Yao, A. Ostman, K. Kappert, N. K. Tonks, and R. M. Touyz Redox-Sensitive Signaling by Angiotensin II Involves Oxidative Inactivation and Blunted Phosphorylation of Protein Tyrosine Phosphatase SHP-2 in Vascular Smooth Muscle Cells From SHR Circ. Res., July 18, 2008; 103(2): 149 - 158. [Abstract] [Full Text] [PDF]

				R. C.M. Siow and A. T. Churchman Adventitial growth factor signalling and vascular remodelling: Potential of perivascular gene transfer from the outside-in Cardiovasc Res, September 1, 2007; 75(4): 659 - 668. [Abstract] [Full Text] [PDF]