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Ursula G. B. Haider,
Thomas U. Roos, Maria I. Kontaridis, Benjamin G.
Neel, Dan Sorescu, Kathy K. Griendling,
Angelika M. Vollmar, and Verena M. Dirsch1
Department of Pharmacy, Center of Drug
Research, University of Munich, Munich, Germany (U.G.B.H., T.U.R., A.M.V., V.M.D.);
Cancer Biology Program, Beth Israel Deaconess Medical Center, Boston,
Massachusetts (M.I.K., B.G.N.); and Department of Medicine, Division of
Cardiology, Emory University, Atlanta, Georgia (D.S., K.K.G.)
trans-Resveratrol (RV), a
polyphenolic stilbene derivative found in grape skin and other food
products, has been proposed to exert beneficial effects in
cardiovascular disease. Our group has shown previously that RV
inhibits angiotensin II (Ang II)-induced Akt activation and,
consequently, vascular smooth muscle cell (VSMC) hypertrophy. In this
work, to identify the molecular target of RV, we investigated the
impact of RV on early signaling cascades in rat aortic VSMCs
triggered by Ang II and epidermal growth factor (EGF). We show that
RV does not influence Ang II-mediated transactivation of EGF-receptor
but potently inhibits EGF-induced phosphorylation of Akt kinase,
suggesting that RV acts downstream of EGF-receptor transactivation in
VSMCs. Recent evidence indicates that the adapter molecule Gab1,
together with the protein tyrosine phosphatase Shp2, is critically
involved in regulating the strength and duration of
phosphatidylinositol-3-kinase (PI3K) and Akt activation upon EGF
stimulation in fibroblasts. Our results show that stimulation of
VSMCs with EGF as well as Ang II leads to a rapid tyrosine
phosphorylation of Gab1 and its association with the p85 subunit of
PI3K. RV attenuates these processes. Experiments performed in
Shp2-deficient fibroblasts revealed that RV does not inhibit EGF-stimulated
Akt activation in these cells, suggesting that Shp2 is necessary for
the inhibitory effect of RV on the PI3K/Akt pathway. Furthermore, RV
treatment activates Shp2. We therefore propose that RV blocks Akt
activation in Ang II- and EGF-stimulated VSMCs by activating Shp2,
thus preventing interaction between Gab1 and PI3K that is necessary
for further signal transduction.
Address correspondence to:
Dr. Verena M. Dirsch, Department of Pharmacy, Center of Drug Research,
Butenandtstrasse 5–13, D-81377 Munich, Germany. E-mail:
Dr. Verena Dirsch
Full article available at
http://molpharm.aspetjournals.org >>
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