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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:894.)
© 2002 American Heart Association, Inc.

Vascular Biology

Reversal of Thrombin-Induced Deactivation of CD39/ATPDase in Endothelial Cells by HMG-CoA Reductase Inhibition

Effects on Rho-GTPase and Adenosine Nucleotide Metabolism

Nicole C. Kaneider; Petra Egger; Stefan Dunzendorfer; Patrizia Noris; Carlo L. Balduini; Donatella Gritti; Giovanni Ricevuti; Christian J. Wiedermann

From the Department of Internal Medicine (N.C.K., P.E., S.D., C.J.W.), University of Innsbruck, Austria; and the Department of Internal Medicine and Therapeutics (P.N., C.L.B., D.G., G.R.), IRCC San Matteo Hospital, University of Pavia, Italy.

Correspondence to Prof Christian J. Wiedermann, MD, Department of Internal Medicine, University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria. E-mail Christian.Wiedermann{at}uibk.ac.at

Abstract— Adenosine triphosphate and diphosphate that activate platelet, leukocyte, and endothelium functions are hydrolyzed by endothelial CD39/ATPDase. Because CD39/ATPDase is downregulated in endothelial cells by inflammation and this may be affected by HMG-CoA reductase inhibitors, we examined the role of cerivastatin and simvastatin in regulation of endothelial CD39/ATPDase expression, metabolism of ATP/ADP, and function in platelets. Thrombin-stimulated endothelial cells in vitro were treated with the statins, and hydrolysis of exogenous ADP and ATP was assessed by high-performance liquid chromatography and malachite green assay. Platelet aggregation studies were performed with endothelial cell supernatants as triggers. CD39/ATPDase surface expression by endothelial cells was determined immunologically by fluorescence-activated cell sorter, mRNA expression by RT-PCR, and thrombin-induced dissociation of Rho-GTPases by Western blotting. Treatment by simvastatin or cerivastatin restored impaired metabolism of exogenous ATP and ADP in thrombin-activated endothelial cells by preventing thrombin-induced downregulation of CD39/ATPDase. In platelet aggregation studies, ATP and ADP supernatants of thrombin-activated endothelial cells were less stimulatory in the presence of statins than in their absence. Data show that statins preserve CD39/ATPDase activity in thrombin-treated endothelial cells involving alterations by statins of Rho-GTPase function and CD39/ATPDase expression. Preservation of adenine nucleotide metabolism may directly contribute to the observed anti-thrombotic and anti-inflammatory actions of statins.

Key Words: atherosclerosis • arterial thrombosis • thrombin • vascular biology • aggregation

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