on March 27, 2003
Arteriosclerosis, Thrombosis, and Vascular Biology. 2003
Published online before print March 27, 2003, doi: 10.1161/01.ATV.0000069236.27911.68
Published online before print March 27, 2003, doi: 10.1161/01.ATV.0000069236.27911.68
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Submitted on February 5, 2003
Accepted on March 13, 2003
c-Src Induces Phosphorylation and Translocation of p47phox. Role in Superoxide Generation by Angiotensin II in Human Vascular Smooth Muscle Cells
R. M. Touyz *;
From the Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Canada.
* To whom correspondence should be addressed. E-mail: touyzr{at}ircm.qc.ca.
Objectives--The aim of this study was to determine molecular mechanisms whereby c-Src regulates angiotensin II (Ang II)-mediated NAD(P)H oxidase-derived ·O2- in human vascular smooth muscle cells (VSMCs).
Methods and Results--VSMCs from human small arteries were studied. Ang II increased NAD(P)H oxidase-mediated generation of ·O2- and H2O2 (P<0.01). PP2, c-Src inhibitor, attenuated these effects by 70% to 80%. Immunoprecipitation of p47phox, followed by immunoblotting with antiphosphoserine antibody, demonstrated a rapid increase (1.5- to 2-fold) in p47phox phosphorylation in Ang II-stimulated cells. This was associated with p47phox translocation from cytosol to membrane, as assessed by immunoblotting and immunofluorescence. PP2 abrogated these effects. Long-term Ang II stimulation (6 to 24 hours) increased NAD(P)H oxidase subunit expression. c-Src inhibition decreased abundance of gp91phox, p22phox, and p47phox. Confirmation of c-Src-dependent regulation of NAD(P)H oxidase was tested in VSMCs from c-Src-/- mice. Ang II-induced ·O2- generation was lower in c-Src-/- than c-Src+/+ counterparts. This was associated with decreased p47phox phosphorylation, blunted Ang II-stimulated NAD(P)H oxidase activation, and failure of Ang II to increase subunit expression.
Conclusions--c-Src regulates NAD(P)H oxidase-derived ·O2- generation acutely by stimulating p47phox phosphorylation and translocation and chronically by increasing protein content of gp91phox, p22phox, and p47phox in Ang II-stimulated cells. These novel findings identify NAD(P)H oxidase subunits, particularly p47phox, as downstream targets of c-Src.
Key words: reactive oxygen species • tyrosine kinases • arteries
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