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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2769.)
© 2007 American Heart Association, Inc.

Thrombosis

Cardiac Glycosides Regulate Endothelial Tissue Factor Expression in Culture

Barbara E. Stähli; Alexander Breitenstein; Alexander Akhmedov; Giovanni G. Camici; Kushiar Shojaati; Nikolay Bogdanov; Jan Steffel; Daniel Ringli; Thomas F. Lüscher; Felix C. Tanner

From Cardiovascular Research (B.E.S., A.B., A.A., G.G.C., K.S., J.S., D.R., T.F.L., F.C.T.), Physiology Institute, University of Zürich; the Center for Integrative Human Physiology (B.E.S., A.B., A.A., G.G.C., K.S., N.B., J.S., D.R., T.F.L., F.C.T.), University of Zürich; Cardiology, Cardiovascular Center (B.E.S., A.B., J.S., T.F.L., F.C.T.), University Hospital Zürich; and the Institue of Veterinary Physiology (N.B.), Vetsuisse Faculty, University of Zürich, Switzerland.

Correspondence to Felix C. Tanner, MD, Cardiovascular Research, Physiology Institute, University of Zürich and Cardiology, University Hospital Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland. E-mail felix.tanner{at}access.unizh.ch

Background— Tissue factor (TF) plays an important role in acute coronary syndromes and stent thrombosis. This study investigates whether Na⁺/K⁺-ATPase regulates TF expression in human endothelial cells.

Methods and Results— Ouabain inhibited tumor necrosis factor (TNF)-–induced endothelial TF protein expression; maximal inhibition occurred at 10^–5 mol/L, reached more than 70%, and was observed throughout the 5 hours stimulation period. The decrease in protein expression was paralleled by a reduced TF surface activity. Similarly, lowering of extracellular potassium concentration inhibited TNF-–induced TF protein expression. In contrast, ouabain did not affect TNF-–induced expression of full-length TF mRNA for up to 5 hours of stimulation; instead, expression of alternatively-spliced TF mRNA was upregulated after 3 and 5 hours of stimulation. Ouabain did not affect TNF-–induced activation of the MAP kinases p38, extracellular signal-regulated kinase (ERK), and c-Jun terminal NH₂ kinase; activation of Akt and p70S6 kinase remained unaltered as well. Similar to the MAP kinases, ouabain did not affect TNF-–induced degradation of IB-. Ouabain had no effect on TF protein degradation.

Conclusions— Na⁺/K⁺-ATPase is required for protein translation of endothelial TF in culture. This observation provides novel insights into posttranscriptional regulation of TF expression.

Inhibition of Na⁺/K⁺-ATPase by ouabain inhibited TNF-–induced endothelial TF protein expression via a reduced protein translation. TF mRNA expression was not inhibited, and TF protein stability remained unaffected. This observation provides novel insights into posttranscriptional regulation of TF expression in culture.

Key Words: Ouabain • translation • thrombosis

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