PT  - JOURNAL ARTICLE
AU  - Ju-Chi Liu
AU  - Cheng-Hsien Chen
AU  - Jin-Jer Chen
AU  - Tzu-Hurng Cheng
TI  - Urotensin II Induces Rat Cardiomyocyte Hypertrophy via the Transient Oxidization of Src Homology 2-Containing Tyrosine Phosphatase and Transactivation of Epidermal Growth Factor Receptor
AID  - 10.1124/mol.109.058297
DP  - 2009 Dec 01
TA  - Molecular Pharmacology
PG  - 1186--1195
VI  - 76
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/76/6/1186.short
4100  - http://molpharm.aspetjournals.org/content/76/6/1186.full
SO  - Mol Pharmacol2009 Dec 01; 76
AB  - Urotensin II (U-II) is implicated in cardiomyocyte hypertrophy, which results in cardiac remodeling. We recently demonstrated that both reactive oxygen species (ROS) generation and epidermal growth factor receptor (EGFR) transactivation play critical roles in U-II signal transduction. However, the detailed intracellular mechanism(s) underlying cardiac hypertrophy and remodeling remain unclear. In this study, we used rat cardiomyocytes treated with U-II to investigate the association between ROS generation and EGFR transactivation. U-II treatment was found to stimulate cardiomyocyte hypertrophy through phosphorylation of EGFR and ROS generation. Apocynin, an NAD(P)H oxidase inhibitor, and N-acetyl cysteine (NAC), an ROS scavenger, both inhibited EGFR transactivation induced by U-II. In contrast, 4-(3′-chloroanilino)-6,7-dimethoxy-quinazoline (AG1478, an EGFR inhibitor) failed to inhibit intracellular ROS generation induced by U-II. Src homology 2-containing tyrosine phosphatase (SHP-2), but not protein tyrosine phosphatase 1B (PTP 1B), was shown to be associated with EGFR during U-II treatment by EGFR coimmunoprecipitation. ROS have been reported to transiently oxidize the catalytic cysteine of phosphotyrosine phosphatases, subsequently inhibiting their activity. We examined the effect of U-II on SHP-2 and PTP 1B in cardiomyocytes using a modified malachite green phosphatase assay. SHP-2, but not PTP 1B, was transiently oxidized during U-II treatment, which could be repressed by NAC treatment. In SHP-2 knockdown cells, U-II-induced phosphorylation of EGFR and myocyte hypertrophy were dramatically elevated, and these effects were not influenced by NAC. Our data suggest that U-II-mediated ROS generation can transiently inhibit SHP-2 activity, thereby facilitating EGFR transactivation and hypertrophic signal transduction in rat cardiomyocytes.© 2009 The American Society for Pharmacology and Experimental Therapeutics