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Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 12, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm061
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Valproic acid interferes with antiviral treatment in human cytomegalovirus-infected endothelial cells

Martin Michaelis, T. Anh, T. Ha, Hans Wilhelm Doerr and Jindrich Cinatl, jr*

Institut für Medizinische Virologie, Klinikum der J.W. Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany

* Corresponding author: phone +49 69 6301 6409; fax +49 69 6301 4302 e-mail Cinatl{at}em.uni-frankfurt.de

Aim: The endothelium represents a natural site of human cytomegalovirus (HCMV) infection involved in viral spreading and persistence. Moreover, HCMV infection of endothelial cells has been associated with different pathological conditions of the cardiovascular system. Here, the influence of the antiepileptic drug valproic acid (VPA) was investigated on HCMV replication in human umbilical vein endothelial cells alone or in combination with the antiviral drugs ganciclovir, cidofovir or foscarnet.

Methods: HCMV replication was observed by immunostaining for viral antigens and by virus yield assay. Protein expression and phosphorylation was examined by Western blot. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye reduction assay.

Results: Therapeutic VPA concentrations (= 1 mM) increased HCMV immediate early antigen, late antigen and viral titres of different endotheliotropic and non-endotheliotropic HCMV strains in a concentration- and time-dependent manner up to 30-fold. Moreover, VPA impaired the antiviral activity of the anti-HCMV drugs ganciclovir, cidofovir and foscarnet. VPA inhibits histone deacetylases (HDAC) and induces HDAC-independently extracellular signal-regulated kinases 1/2 (ERK 1/2) phosphorylation in endothelial cells. Both effects observed, HCMV stimulation and interference with antiviral drugs, depend on HDAC inhibition but not on ERK 1/2 phosphorylation.

Conclusion: These findings suggest to carefully monitor the frequency of HCMV reactivation in cardiovascular patients treated with VPA (or other HDAC inhibitors) in comparison to control individuals.

Time for primary review: 25


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