Urotensin Ii Induces Rat Cardiomyocyte Hypertrophy Via the Transient Oxidization of Src Homology 2-Containing Tyrosine Phosphatase and Transactivation of Epidermal Growth Factor Receptor
Resource
MOLECULAR PHARMACOLOGY v.76 n.6 pp.1186-1195
Journal
Molecular Pharmacology
Pages
1186-1195
Date Issued
2009
Date
2009
Author(s)
LIU, JU-CHI
CHEN, CHENG-HSIEN
CHEN, JIN -JER
CHENG, TZU-HURNG
Abstract
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.
Type
journal article