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Ribavirin inhibits angiogenesis by tetrahydrobiopterin depletion

Martin Michaelis^*, Ruth Michaelis, Tatyana Suhan^*, Helmut Schmidt, Annisuddin Mohamed, Hans Wilhelm Doerr^* and Jindrich Cinatl, Jr.^*,1

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

Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe Universität, Theodor-Stern-Kai-7, Frankfurt am Main, Germany;

Pharmazentrum Frankfurt, Institut für Klinische Pharmakologie, Klinikum der J.W. Goethe Universität, Theodor-Stern-Kai-7, Frankfurt am Main, Germany

¹Correspondence: Institut für Medizinische Virologie, Klinikum der Johann Wolfgang Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany. E-mail: cinatl{at}em.uni-frankfurt.de

Ribavirin is a broad-spectrum antiviral drug that is used to treat hepatitis C virus (HCV)-infected patients. The virological response after ribavirin treatment appears to be insufficient to fully explain ribavirin-induced beneficial effects. Angiogenesis plays a pathogenic role in HCV-induced liver damage. Here, we investigated the influence of therapeutic ribavirin concentrations on angiogenesis. Ribavirin inhibited endothelial cell tube formation in vitro and vessel formation in the chick chorioallantoic membrane assay in vivo. Ribavirin inhibits inosine monophosphate dehydrogenase, which causes depletion of cellular GTP and in turn reduction of cellular tetrahydrobiopterin levels. The availability of tetrahydrobiopterin limits NO production by endothelial NO synthase. Ribavirin reduced levels of tetrahydrobiopterin (as revealed by HPLC), NO (as revealed by electron spin resonance spectroscopy), and cGMP (as revealed by RIA) in endothelial cells. Addition of tetrahydrobiopterin or NO prevented ribavirin-induced tube formation inhibition. In conclusion, angiogenesis inhibition by ribavirin has not been described before. This inhibition may contribute to ribavirin-induced pharmacological effects including adverse events.—Michaelis, M., Michaelis, R., Suhan, T., Schmidt, H., Mohamed, A., Doerr, H. W., Cinatl, Jr., J. Ribavirin inhibits angiogenesis by tetrahydrobiopterin depletion.

Key Words: endothelial cell • hepatitis C • inosine monophospate dehydrogenase • NO

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