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Vol. 289, Issue 3, 1480-1486, June 1999

The Protein Phosphatase Inhibitor Cantharidin Alters Vascular Endothelial Cell Permeability1

Jörg Knapp, Peter Bokník, Iva Lüss, Sabine Huke, Bettina Linck, Hartmut Lüss, Frank U. Müller, Thorsten Müller, Peter Nacke, Thomas Noll, Hans M. Piper, Wilhelm Schmitz, Ute Vahlensieck and Joachim Neumann

Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität Münster, Germany (J.K., P.B., I.L., S.H., B.L., H.L., F.U.M., T.M., P.N., W.S., U.V., J.N.); and Institut für Physiologie, Justus-Liebig Universität Giebeta en, Aulweg 129, Giebeta en, Federal Republic of Germany (T.N., H.M.P.)

In this study, we characterized the effects of the protein phosphatases type 1 (PP 1) and type 2A (PP 2A) inhibitor cantharidin in endothelial cells. We identified catalytic subunits of PP 1alpha , PP 2Aalpha , and PP 2Abeta immunologically in bovine aortic endothelial cells. Moreover, we detected mRNAs coding for catalytic subunits of PP 1alpha , PP 1beta , and PP 2Aalpha by hybridization with specific DNA probes in total RNA from these cells. Okadaic acid and cantharidin inhibited the activities of catalytic subunits of PP 1 (okadaic acid, 0.01-1 µM; cantharidin, 1-100 µM) and PP 2A (okadaic acid, 0.1 nM to 1 µM; cantharidin, 0.1-100 µM) separated by column chromatography in a concentration-dependent manner. Moreover, cantharidin (1 µM to 1 mM) increased the phosphorylation state of endothelial proteins including the regulatory light chains of myosin without affecting cytosolic calcium concentrations. Cantharidin (5-100 µM) increased the permeability of cultured endothelial cells in a time- and concentration-dependent manner. We suggest that inhibition of PP 1 and PP 2A activities by cantharidin increases endothelial permeability by enhancing the phosphorylation state of endothelial regulatory proteins. Thus, cantharidin might be a useful tool to study the function of protein phosphatases in endothelial barrier function.

0022-3565/99/2893-1480$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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