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(Circulation. 2000;102:2803.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Simvastatin Improves Disturbed Endothelial Barrier Function

Geerten P. van Nieuw Amerongen, PhD; Mario A. Vermeer, BSc; Pascale Nègre-Aminou, PhD; Jan Lankelma, PhD; Jef J. Emeis, PhD; Victor W. M. van Hinsbergh, PhD

From the Gaubius Laboratory TNO-PG (G.P.v.N.A., M.A.V., P.N.-A., J.J.E., V.W.M.v.H.), Leiden; the Department of Physiology (G.P.v.N.A., V.W.M.v.H.), Institute for Cardiovascular Research, Vrije Universiteit, Amsterdam; and the Department of Medical Oncology (J.L.), University Hospital, Vrije Universiteit, Amsterdam, the Netherlands

Correspondence to Prof Dr V.W.M. van Hinsbergh, Gaubius Laboratory TNO-PG, PO Box 2215, 2301 CE Leiden, Netherlands. E-mail VWM.VANHINSBERGH{at}PG.TNO.NL

Background—Recent clinical trials have established that inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) reduce the risk of acute coronary events. These effects of statins cannot be fully explained by their lipid-lowering potential. Improved endothelial function may contribute to the positive effects of statin treatment.

Methods and Results—In the present study, we report that simvastatin reduces endothelial barrier dysfunction, which is associated with the development of atherosclerosis. Treatment of human umbilical vein endothelial cells for 24 hours with 5 µmol/L simvastatin reduced the thrombin-induced endothelial barrier dysfunction in vitro by 55±3%, as assessed by the passage of peroxidase through human umbilical vein endothelial cell monolayers. Similar effects were found on the thrombin-induced passage of ¹²⁵I-LDL through human aortic endothelial cell monolayers. This reduction in barrier dysfunction by simvastatin was both dose and time dependent and was accompanied by a reduction in the thrombin-induced formation of stress fibers and focal adhesions and membrane association of RhoA. Simvastatin treatment had no effect on intracellular cAMP levels. In Watanabe heritable hyperlipidemic rabbits, treatment for 1 month with 15 mg/kg simvastatin reduced vascular leakage in both the thoracic and abdominal part of the aorta, as evidenced by the Evans blue dye exclusion test. The decreased permeability was not accompanied by a reduction of oil red O–stainable atherosclerotic lesions.

Conclusions—These data show that simvastatin, in a relatively high concentration, improves disturbed endothelial barrier function both in vitro and in vivo. The data also support the beneficial effects of simvastatin in acute coronary events by mechanisms other than its lipid-lowering effect.

Key Words: cells • statins • endothelium • thrombin

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