Statins blunt thrombin-induced down-regulation of endothelial nitric oxide synthase expression in human endothelial cells.
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 micromol/L). Cerivastatin (10 micromol/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 micromol/L) and cerivastatin (10 micromol/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.
Eto
Masato
M
Cardiology, Cardiovascular Centre, University Hospital, University of Zürich, Zürich, Switzerland.
Rathgeb
Lisa
L
Cosentino
Francesco
F
Kozai
Toshiyuki
T
Lüscher
Thomas F
TF
D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D019821:Simvastatin / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D019821:Simvastatin; C086276:cerivastatin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D013917:Thrombin; D020742:rhoA GTP-Binding Protein