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Molecular Mechanisms of Oxidative Stress‐induced STAT3 Activation in Endothelial Cells
Author(s) -
Bartoli Manuela,
Platt Daniel H,
Lemtalsi Tahira,
Remessy Azza El,
Rojas Modesto,
Caldwell Robert W,
Caldwell Ruth B
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a703-c
Subject(s) - oxidative stress , reactive oxygen species , tyrosine phosphorylation , stat3 , phosphorylation , superoxide dismutase , chemistry , protein tyrosine phosphatase , microbiology and biotechnology , oxidative phosphorylation , catalase , biochemistry , biology
We and others have established that STAT3 is a critical mediator of VEGF function and expression in microvascular endothelial cells (EC). In inflammatory diseases, including diabetic microangiopathies, enhanced STAT3 activation has been correlated with increased oxidative stress and VEGF expression. Here we wanted to determine whether and how elevation of reactive oxygen species (ROS) formation affects the activation of STAT3 in endothelial cells. EC were cultured in the presence of 25mM D‐glucose for 24 hours and then challenged with 20ng/ml VEGF for different times. This treatment resulted in enhanced reactive oxygen species (ROS) formation, as demonstrated by hydroethidine staining. Furthermore, western blotting and immunoprecipitation analyses revealed that EC cultured in the presence of HG showed sustained VEGF‐dependent STAT3 tyrosine phosphorylation which correlated with decreased phosphorylation of the tyrosine phosphatase SHP‐1 and blockade of STAT3/SHP‐1 interaction. These HG/ oxidative stress effects were blocked by concomitant treatment of EC with the antioxidants superoxide dismutase and catalase. In addition, antisense‐mediated inhibition of SHP‐1 expression resulted in constitutive STAT3 tyrosine phosphorylation. In conclusion, these results demonstrate a key role for SHP‐1 in the regulation of VEGF‐dependent STAT3 activation in EC and suggest that oxidative stress‐mediated STAT3 activation occurs through inhibition of SHP‐1.