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Research ArticleArticle

Urotensin II Induces Rat Cardiomyocyte Hypertrophy via the Transient Oxidization of Src Homology 2-Containing Tyrosine Phosphatase and Transactivation of Epidermal Growth Factor Receptor

Ju-Chi Liu, Cheng-Hsien Chen, Jin-Jer Chen and Tzu-Hurng Cheng
Molecular Pharmacology December 2009, 76 (6) 1186-1195; DOI: https://doi.org/10.1124/mol.109.058297
Ju-Chi Liu
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Cheng-Hsien Chen
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Jin-Jer Chen
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Tzu-Hurng Cheng
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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.

Footnotes

  • This work was supported by the National Science Council [Grant NSC 95-2314-B-039-048-MY2], the New Century Health Care Promotion Foundation Medical Research Award [Grant 97-TMU-IAC-021], and the China Medical University [Grant CMU97-233], Taiwan, R.O.C.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.058297

  • ABBREVIATIONS:

    U-II
    urotensin II
    ROS
    reactive oxygen species
    EGFR
    epidermal growth factor receptor
    ERK
    extracellular signal-regulated kinase
    PTP
    protein tyrosine phosphatase
    AG-1478
    4-(3′-chloroanilino)-6,7-dimethoxy-quinazoline
    NAC
    N-acetyl-cysteine
    DAPI
    4′,6-diamidino-2-phenylindole
    PBS
    phosphate-buffered saline
    DCFH
    2′,7′-dichlorodihydrofluorescein
    DCF
    2′,7′-dichlorofluorescein
    IAA
    iodoacetic acid
    siRNA
    small interfering RNA
    GFP
    green fluorescent protein
    U0126
    1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene
    SHP-2
    Src homology 2-containing tyrosine phosphatase.

    • Received June 3, 2009.
    • Accepted September 15, 2009.
  • © 2009 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (6)
Molecular Pharmacology
Vol. 76, Issue 6
1 Dec 2009
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Research ArticleArticle

Urotensin II Induces Rat Cardiomyocyte Hypertrophy via the Transient Oxidization of Src Homology 2-Containing Tyrosine Phosphatase and Transactivation of Epidermal Growth Factor Receptor

Ju-Chi Liu, Cheng-Hsien Chen, Jin-Jer Chen and Tzu-Hurng Cheng
Molecular Pharmacology December 1, 2009, 76 (6) 1186-1195; DOI: https://doi.org/10.1124/mol.109.058297

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Research ArticleArticle

Urotensin II Induces Rat Cardiomyocyte Hypertrophy via the Transient Oxidization of Src Homology 2-Containing Tyrosine Phosphatase and Transactivation of Epidermal Growth Factor Receptor

Ju-Chi Liu, Cheng-Hsien Chen, Jin-Jer Chen and Tzu-Hurng Cheng
Molecular Pharmacology December 1, 2009, 76 (6) 1186-1195; DOI: https://doi.org/10.1124/mol.109.058297
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