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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 26; no. 12; pp. 2644 - 2651
• Main Authors: Kappert, Kai, Sparwel, Jan, Sandin, Åsa, Seiler, Alexander, Siebolts, Udo, Leppänen, Olli, Rosenkranz, Stephan, Östman, Arne
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.12.2006; Hagerstown, MD Lippincott
• Subjects: Acetylcysteine - pharmacology; Animals; Antioxidants - pharmacology; Associated diseases and complications; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Movement - drug effects; Cell Movement - physiology; Cell Proliferation - drug effects; Cells, Cultured; Coronary Restenosis - genetics; Coronary Restenosis - metabolism; Cyclic N-Oxides - pharmacology; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Gene Expression Regulation - physiology; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - genetics; Gene Expression Regulation, Enzymologic - physiology; Hydrogen Peroxide - pharmacology; Male; Medical sciences; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; neointima formation; platelet-derived growth factor; Platelet-Derived Growth Factor - genetics; Platelet-Derived Growth Factor - metabolism; protein tyrosine phosphatase; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Receptors, Platelet-Derived Growth Factor - genetics; Receptors, Platelet-Derived Growth Factor - metabolism; restenosis; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - physiology; Spin Labels; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the heart; VSMC; neointima formation; Cell culture; Enzyme; protein tyrosine phosphatase; Phosphoric monoester hydrolases; Cardiovascular disease; platelet-derived growth factor; Esterases; Antioxidant; Vascular disease; Restenosis; Atherosclerosis; Hydrolases; VSMC; Platelet derived growth factor; Protein-tyrosine-phosphatase
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/01.ATV.0000246777.30819.85

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 β-receptor status, and PTP expression and activity. NAC treatment prevented H2O2-induced PTP inhibition, and reduced H2O2- and ligand-induced PDGF β-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 β-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.