Circulation. 2002;105:1756-1759
Published online before print April 1, 2002, doi: 10.1161/01.CIR.0000015465.73933.3B
Published online before print April 1, 2002, doi: 10.1161/01.CIR.0000015465.73933.3B
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(Circulation. 2002;105:1756.)
© 2002 American Heart Association, Inc.
Brief Rapid Communications |
Statin Prevents Tissue Factor Expression in Human Endothelial Cells
Role of Rho/Rho-Kinase and Akt Pathways
From the Division of Cardiology (M.E., T.K., F.C, T.F.L.), CardioVascular Center, University Hospital and Cardiovascular Research (M.E., T.K., F.C., H.J., T.F.L.), Institute of Physiology, University of Zurich, Zurich, Switzerland; the Department of Experimental Medicine and Pathology (F.C.), "La Sapienza" University, Rome, Italy; and Department of Neuromed (F.C.), Pozzilli, Italy.
Correspondence to Thomas F. Lüscher, MD, Division of Cardiology, University Hospital, Ramistrasse 100, CH-8091 Zurich, Switzerland. E-mail cardiotfl{at}gmx.ch
Background— Tissue factor plays a pivotal role in thrombus formation in acute coronary syndromes. However, the regulatory mechanisms underlying tissue factor expression are poorly understood. Statins are effective in patients with acute coronary syndromes. Hence, the aim of this study was to clarify in human endothelial cells the signaling pathways of thrombin-induced tissue factor expression and potential inhibitory effects of statins.
Methods and Results— In human aortic endothelial cells, simvastatin prevented tissue factor induction by thrombin (4 U/mL) in a concentration-dependent manner. The increase in tissue factor activity on the cell surface was also blocked by simvastatin. Simvastatin also prevented the upregulation of tissue factor expression and activity in human aortic smooth muscle cells. Mevalonate (100 µmol/L) reversed the inhibitory effect of simvastatin on tissue factor expression. Thrombin induced rapid activation of Rho A and p38 MAP kinase. The Rho-kinase inhibitor Y-27632 and the p38 MAP kinase inhibitor SB203580 prevented tissue factor induction. Akt was dephosphorylated by thrombin; the phosphoinositol 3-kinase inhibitor wortmannin enhanced its dephosphorylation as well as thrombin-induced tissue factor expression. Simvastatin prevented thrombin-induced Rho A activation but not p38 MAP kinase activation. Akt dephosphorylation by thrombin was blocked by both simvastatin and Y-27632.
Conclusions— Endothelial tissue factor induction by thrombin is regulated by Rho/Rho-kinase, Akt, and p38 MAP kinase. Simvastatin prevents its induction through inhibition of Rho/Rho-kinase and activation of Akt. These findings provide new insights into the action of statins in acute coronary syndromes.
Key Words: endothelium • pharmacology • signal transduction • thrombosis
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