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 p130casby increasing protein tyrosine phosphatase-proline, glutamate, serine, and threonine sequence protein (PTP-PEST) activity, which leads to the suppression of agonist-induced H2O2elevation 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 H2O2levels and 2) NO suppresses IGF-I-induced H2O2elevation by decreasing Rac1 activity via increased PTP-PEST activity and dephosphorylation of p130cas. We report that IGF-I induces phosphorylation of p130casand 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)-p130casand antagonized by the expression of dn-PTP-PEST or p130cas. We conclude that IGF-I induces rat aortic SMC motility by increasing phosphotyrosine levels of p130casand activating Rac1 and that NO decreases motility by activating PTP-PEST, inducing dephosphorylating p130cas, and decreasing Rac1 activity. Decreased Rac1 activity lowers intracellular H2O2levels, thus attenuating cell motility.