Share this article on:

Statins Blunt Thrombin-induced Down-regulation of Endothelial Nitric Oxide Synthase Expression in Human Endothelial Cells

Eto, Masato MD* †; Rathgeb, Lisa; Cosentino, Francesco MD* † ‡; Kozai, Toshiyuki MD* †; Lüscher, Thomas F. MD, FRCP* †

Journal of Cardiovascular Pharmacology: May 2006 - Volume 47 - Issue 5 - p 663-667
doi: 10.1097/01.fjc.0000211754.54691.f3
Original Articles

Thrombin plays a pivotal role in the pathophysiology of acute coronary syndromes by mediating thrombus formation and endothelium-dependent vasomotor dysfunction. In human endothelial cells, prolonged incubation with thrombin down-regulates endothelial nitric oxide synthase (eNOS) expression via activation of Rho. Statins are effective in patients with acute coronary syndromes. These beneficial effects are attributed to their pleiotropic effects and also to an improved lipid profile. We hypothesized that statins may prevent the down-regulation of eNOS induced by thrombin in human endothelial cells. Human umbilical vein endothelial cells were used. Expression and activity of eNOS protein were evaluated by Western blotting and L-citrulline assay, respectively. Rho A membrane translocation was evaluated by Wesern blotting after fractionation. Stimulation of human umbilical vein endothelial cells with thrombin (4 U/mL, 24 h) significantly decreased eNOS expression. The addition of simvastatin significantly prevented thrombin-induced down-regulation of eNOS expression in a concentration-dependent manner (100 nmol/L to 10 μmol/L). Cerivastatin (10 μmol/L) also reversed the down-regulation of eNOS by thrombin. Both simvastatin and cerivastatin-blocked thrombin-induced decrease in NOS activity. Stimulation with thrombin (4 U/mL, 10 min) significantly increased the membrane translocation of Rho A. Simvastatin (10 μmol/L) and cerivastatin (10 μmol/L) significantly decreased thrombin-induced membrane translocation of Rho A. Therefore, statins blunt thrombin-induced down-regulation of eNOS expression in human endothelial cells. This finding provides a novel mechanism of the pleiotropic effects of statins, which may be beneficial for patients with acute coronary syndromes.

*Cardiology, Cardiovascular Centre, University Hospital

Cardiovascular Research, Institute of Physiology, University of Zürich, Zürich, Switzerland

Cardiology, The 2nd Faculty of Medicine, “La Sapienza” University, Rome, Italy

Supported by the Swiss National Research Foundation (Grant Nr.32-67202.01), the Swiss Heart Foundation and the Roche Research Foundation. Dr Eto was supported by an educational grant from Merck. Dr Kozai was supported by an educational grant from Bayer Pharmaceuticals.

Reprints: Thomas F. Lüscher, MD, FRCP, Cardiovascular Center, University Hospital, Rämistrasse 100, CH-8091 Zürich, Switzerland (e-mail: cardiotfl@gmd.ch)

Received for publication February 3, 2004; accepted December 24, 2004

First two authors contributed equally to this study.

© 2006 Lippincott Williams & Wilkins, Inc.