title: Resveratrol inhibits angiotensin II- and epidermal growth factor-mediated Akt activation: role of Gab1 and Shp2.
abstract: 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.
authors.affiliation: Department of Pharmacy, Center of Drug Research, Butenandtstrasse 5-13, D-81377 Munich, Germany.
authors.forename: Ursula G B
authors.initials: UG
authors.lastname: Haider
authors.forename: Thomas U
authors.initials: TU
authors.lastname: Roos
authors.forename: Maria I
authors.initials: MI
authors.lastname: Kontaridis
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Dan
authors.initials: D
authors.lastname: Sorescu
authors.forename: Kathy K
authors.initials: KK
authors.lastname: Griendling
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
mesh_terms: D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490897:Gab1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D013267:Stilbenes; D000804:Angiotensin II; D004815:Epidermal Growth Factor; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C516727:Ptpn11 protein, rat; D000077185:Resveratrol