title: Nitric oxide attenuates IGF-I-induced aortic smooth muscle cell motility by decreasing Rac1 activity: essential role of PTP-PEST and p130cas.
abstract: Recent data support the hypothesis that reactive oxygen species (ROS) play a central role in the initiation and progression of vascular diseases. An important vasoprotective function related to the regulation of ROS levels appears to be the antioxidant capacity of nitric oxide (NO). We previously reported that treatment with NO decreases phosphotyrosine levels of adapter protein p130(cas) by increasing protein tyrosine phosphatase-proline, glutamate, serine, and threonine sequence protein (PTP-PEST) activity, which leads to the suppression of agonist-induced H(2)O(2) elevation and motility in cultured rat aortic smooth muscle cells (SMCs). The present study was performed to investigate the hypotheses that 1) IGF-I increases the activity of the small GTPase Rac1 as well as H(2)O(2) levels and 2) NO suppresses IGF-I-induced H(2)O(2) elevation by decreasing Rac1 activity via increased PTP-PEST activity and dephosphorylation of p130(cas). We report that IGF-I induces phosphorylation of p130(cas) and activation of Rac1 and that NO attenuates these effects. The effects of NO are mimicked by the overexpression of PTP-PEST or dominant-negative (dn)-p130(cas) and antagonized by the expression of dn-PTP-PEST or p130(cas). We conclude that IGF-I induces rat aortic SMC motility by increasing phosphotyrosine levels of p130(cas) and activating Rac1 and that NO decreases motility by activating PTP-PEST, inducing dephosphorylating p130(cas), and decreasing Rac1 activity. Decreased Rac1 activity lowers intracellular H(2)O(2) levels, thus attenuating cell motility.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, 894 Union Ave., Memphis, 38163, USA.
authors.forename: Alice-Corina
authors.initials: AC
authors.lastname: Ceacareanu
authors.forename: Bogdan
authors.initials: B
authors.lastname: Ceacareanu
authors.forename: Daming
authors.initials: D
authors.lastname: Zhuang
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Chang
authors.forename: Ramesh M
authors.initials: RM
authors.lastname: Ray
authors.forename: Leena
authors.initials: L
authors.lastname: Desai
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Chapman
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waters
authors.forename: Aviv
authors.initials: A
authors.lastname: Hassid
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002465:Cell Movement; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014226:Triazenes / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; C493843:Bcar1 protein, rat; D050719:Crk-Associated Substrate Protein; D020030:Nitric Oxide Donors; D016877:Oxidants; D014226:Triazenes; D019000:Phosphotyrosine; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; D006861:Hydrogen Peroxide; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D017027:Protein Tyrosine Phosphatases; C516740:Ptpn12 protein, rat; D020830:rac1 GTP-Binding Protein