Simvastatin improves disturbed endothelial barrier function

Background-Recent clinical trials have established that inhibitors of the e nzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) reduce the risk of acute coronary events. These effects of statins cannot be fully exp lained 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 reduce s endothelial barrier dysfunction, which is associated with the development of atherosclerosis. Treatment of human umbilical vein endothelial cells fo r 24 hours with 5 mu mol/L simvastatin reduced the thrombin-induced endothe lial barrier dysfunction in vitro by 55+/-3%, as assessed by the passage of peroxidase through human umbilical vein endothelial cell monolayers. Simil ar effects were found on the thrombin-induced passage of I-125-LDL through human aortic endothelial cell monolayers. This reduction in barrier dysfunc tion by simvastatin was both dose and time dependent and was accompanied by a reduction in the thrombin-induced formation of stress fibers and focal a dhesions and membrane association of RhoA. Simvastatin treatment had no eff ect on intracellular cAMP levels. In Watanabe heritable hyperlipidemic rabb its, treatment for 1 month with 15 mg/kg simvastatin reduced vascular leaka ge in both the thoracic and abdominal part of the aorta, as evidenced by th e Evans blue dye exclusion test. The decreased permeability was not accompa nied by a reduction of oil red O-stainable atherosclerotic lesions. Conclusions-These data show that simvastatin, in a relatively high concentr ation, 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.