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Vol. 63, Issue 4, 925-932, April 2003

Resveratrol Increases Serine15-Phosphorylated but Transcriptionally Impaired p53 and Induces a Reversible DNA Replication Block in Serum-Activated Vascular Smooth Muscle Cells

Ursula G. B. Haider, Dan Sorescu, Kathy K. Griendling, Angelika M. Vollmar, and Verena M. Dirsch

Department of Pharmacy, Center of Drug Research, University of Munich, Munich, Germany (U.G.B.H., A.M.V., V.M.D.); and Department of Medicine, Division of Cardiology, Emory University, Atlanta, Georgia (D.S., K.K.G.)

Resveratrol (RV), a polyphenolic stilbene derivative, has been proposed to exert a plethora of beneficial cardiovascular effects. Of these, in particular, inhibition of vascular smooth muscle cell (VSMC) proliferation shows great promise for preventing cardiovascular disease. In the present study, we show that RV leads to a reversible arrest in early S phase of the VSMC cycle, accompanied by an accumulation of hyperphosphorylated retinoblastoma protein. In contrast to studies with other cell systems, RV decreases cellular levels of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1. This is of particular interest because phosphorylated p53 protein (serine15) is strongly enhanced by this substance. We further found that RV only slightly inhibits phosphorylation of Erk 1/2, protein kinase B/Akt, and p70S6 kinase upon serum stimulation. Thus, inhibition of these kinases is not likely to contribute to the cell cycle effect of RV. Importantly, the observed S phase arrest is not linked to an increase in apoptotic cell death: there was no detectable increase in apoptotic nuclei and in levels of the proapoptotic protein Bax. This is the first study elucidating the molecular pathways mediating the antiproliferative properties of RV in VSMCs.

Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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