Resveratrol blocks Akt activation in angiotensin II-or EGF-stimulated vascular smooth muscle cells in a redox-independent manner

Resveratrol (RV), an antioxidant, inhibits angiotensin II (Ang II)-induced hypertrophy and Ang II- or epidermal growth factor (EGF)-induced Akt phosphorylation in rat vascular smooth muscle cells (VSMCs). Both signalling pathways are reported to utilize reactive oxygen species (ROS). The aim of this...

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Published in:	Cardiovascular research Vol. 90; no. 1; pp. 140 - 147
Main Authors:	SCHREINER, Cornelia E, KUMERZ, Mario, GESSLBAUER, Julia, SCHACHNER, Daniel, JOA, Helge, ERKER, Thomas, ATANASOV, Atanas G, HEISS, Elke H, DIRSCH, Verena M
Format:	Journal Article
Language:	English
Published:	Oxford Oxford University Press 01-04-2011
Subjects:	Analysis of Variance Angiotensin II - metabolism Animals Antioxidants - pharmacology Biological and medical sciences Cardiology. Vascular system Cell Shape - drug effects Cells, Cultured Enzyme Activation Epidermal Growth Factor - metabolism Hydrogen Peroxide - metabolism Male Medical sciences Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - enzymology Muscle, Smooth, Vascular - pathology Myocytes, Smooth Muscle - drug effects Myocytes, Smooth Muscle - enzymology Myocytes, Smooth Muscle - pathology NADH, NADPH Oxidoreductases - metabolism NADPH Oxidase 1 NADPH Oxidase 4 NADPH Oxidases - genetics NADPH Oxidases - metabolism Original Oxidation-Reduction Phosphorylation Proto-Oncogene Proteins c-akt - metabolism Rats Rats, Sprague-Dawley RNA Interference Signal Transduction - drug effects Stilbenes - pharmacology Time Factors Transfection Smooth muscle Redox-regulation Activation Phlebology Regulation(control) Epidermal growth factor Blood vessel Resveratrol Block Circulatory system Angiotensin II Cardiology Cell Vascular smooth muscle cells
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Summary:	Resveratrol (RV), an antioxidant, inhibits angiotensin II (Ang II)-induced hypertrophy and Ang II- or epidermal growth factor (EGF)-induced Akt phosphorylation in rat vascular smooth muscle cells (VSMCs). Both signalling pathways are reported to utilize reactive oxygen species (ROS). The aim of this study was to show whether RV reduces the ROS level in Ang II- or EGF-activated VSMCs and whether reduction of ROS causes the impeded signalling towards Akt in the presence of RV. We show here that RV reduces intracellular ROS and extracellular H₂O₂ release from VSMCs as measured using 2',7'-dichlorodihydrofluorescein-diacetate and Amplex Red™. Since NADPH oxidases (Nox) 1 and 4 are major ROS sources in VSMCs, we examined their need for Akt phosphorylation in response to Ang II or EGF. Experiments using the blocking peptide gp91ds-tat verified a role for Nox1 in Ang II signalling towards Akt, but excluded a role for Nox1 in the respective EGF signalling. A small interfering RNA-mediated knock-down of Nox4 showed that Nox4 was not required for Ang II- or EGF-induced Akt phosphorylation. Use of the flavoprotein inhibitor diphenyleneiodonium, N-acetyl-cysteine, and non-antioxidant RV derivatives revealed that the antioxidant capacity of RV is not required for the inhibition of Akt phosphorylation, in both rat and human VSMCs. Thus, although RV acts as an antioxidant, the antihypertrophic response of RV in VSMCs and the signalling downstream of the EGF receptor towards Akt seem to be largely redox independent.
ISSN:	0008-6363 1755-3245
DOI:	10.1093/cvr/cvq355