P139	Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells.
1M.Michaelis, 2U.R.Michaelis, 1F.Rothweiler, 3D.Eikel, 4M.Zörnig, 3H.Nau, 2I.Fleming, 1H.W.Doerr, 1J.Cinatl jr.
1Klinikum der J.W. Goethe-Universität/Institut für Medizinische Virologie, Frankfurt/Main, DE; 2Klinikum der J.W. Goethe-Universität/Institut für Kardiovaskuläre Physiologie, Frankfurt/Main, DE; 3Stiftung Tierärztliche Hochschule Hannover/Institut für Lebensmitteltoxikologie und Chemische Analytik, Hannover, DE; 4Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Frankfurt/Main, DE.

The histone deacetylase (HDAC) inhibitor valproic acid (VPA) was recently shown to inhibit angiogenesis without being toxic to endothelial cells. Here, we show that VPA increased extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation in human umbilical vein endothelial cells (HUVEC). The investigation of structurally modified VPA derivatives revealed that the induction of ERK 1/2 phosphorylation was not correlated to HDAC inhibition. PD98059, a pharmacological inhibitor of the mitogen-activated protein kinase kinase 1/2 (MEK 1/2), prevented the VPA-induced ERK 1/2 phosphorylation. ERK 1/2 phosphorylation is an anti-apoptotic event in endothelial cells. In concordance, VPA induced phosphorylation of the anti-apoptotic protein Bcl-2 and inhibited serum starvation-induced mitochondrial cytochrome c release and subsequently HUVEC apoptosis. Inhibition of ERK 1/2 phosphorylation prevented Bcl-2 phosphorylation and VPA-induced protection from apoptosis.

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