30 Citations (Scopus)


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-IIinduced 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.

Original languageEnglish
Pages (from-to)1186-1195
Number of pages10
JournalMolecular Pharmacology
Issue number6
Publication statusPublished - Dec 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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