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.
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Abbreviations
- bFGF:
-
basic fibroblast growth factor
- CAM:
-
chick chorioallantoic membrane
- eNOS:
-
endothelial nitric oxide synthase
- ERK 1/2:
-
extracellular signal-regulated kinases 1/2
- FCS:
-
foetal calf serum
- HDAC:
-
histone deacetylases
- HDACI:
-
histone deacetylase inhibitor
- HUVEC:
-
human umbilical vein endothelial cells
- IMDM:
-
Iscove's modified Dulbecco's medium
- MEK 1/2:
-
mitogen-activated protein kinase kinase 1/2
- TSA:
-
trichostatin A
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Acknowledgements
We gratefully acknowledge the support of the ‘Hilfe für krebskranke Kinder Frankfurt eV’ and its foundation ‘Frankfurter Stiftung für krebskranke Kinder’. The work was further supported by the Arthur und Margarete Ebert-Stiftung, the Deutsche Forschungsgemeinschaft, the EU-Research Training Network ‘Nutriceptors’ Contract HPRN-CT-2002-00268, and by the Edith von Heyden-Vermächtnis.
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Michaelis, M., Suhan, T., Michaelis, U. et al. Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells. Cell Death Differ 13, 446–453 (2006). https://doi.org/10.1038/sj.cdd.4401759
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DOI: https://doi.org/10.1038/sj.cdd.4401759
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