title: Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells.
abstract: The histone deacetylase (HDAC) inhibitor valproic acid (VPA) was recently shown to inhibit angiogenesis, but displays no toxicity in endothelial cells. Here, we demonstrate that VPA increases 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 is not correlated to HDAC inhibition. PD98059, a pharmacological inhibitor of the mitogen-activated protein kinase kinase 1/2, prevented the VPA-induced ERK 1/2 phosphorylation. In endothelial cells, ERK 1/2 phosphorylation is known to promote cell survival and angiogenesis. Our results showed that VPA-induced ERK 1/2 phosphorylation in turn causes phosphorylation of the antiapoptotic protein Bcl-2 and inhibits serum starvation-induced HUVEC apoptosis and cytochrome c release from the mitochondria. Moreover, the combination of VPA with PD98059 synergistically inhibited angiogenesis in vitro and in vivo.
authors.affiliation: Institut für Medizinische Virologie, Klinikum der J.W. Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Michaelis
authors.forename: T
authors.initials: T
authors.lastname: Suhan
authors.forename: U R
authors.initials: UR
authors.lastname: Michaelis
authors.forename: K
authors.initials: K
authors.lastname: Beek
authors.forename: F
authors.initials: F
authors.lastname: Rothweiler
authors.forename: L
authors.initials: L
authors.lastname: Tausch
authors.forename: O
authors.initials: O
authors.lastname: Werz
authors.forename: D
authors.initials: D
authors.lastname: Eikel
authors.forename: M
authors.initials: M
authors.lastname: Zörnig
authors.forename: H
authors.initials: H
authors.lastname: Nau
authors.forename: I
authors.initials: I
authors.lastname: Fleming
authors.forename: H W
authors.initials: HW
authors.lastname: Doerr
authors.forename: J
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D014635:Valproic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one