Abstract 12774: HMG-CoA Reductase Inhibitors Exert the Pleiotropic Effects through SmgGDS Up-regulation with a Resultant Rac1 Degradation and Reduced Oxidative Stress in vitro and in vivo
Background: Although HMG-CoA reductase inhibitors (statins) are used worldwide, the molecular mechanisms of their pleiotropic effects independent of cholesterol-lowering effects remain to be fully clarified. We have previously demonstrated that the pleiotropic effects of low-dose statins are mediated through inhibition of the Rac1 signaling pathway rather than the Rho/Rho-kinase pathway. In this study, we tested our hypothesis that small GTP-binding protein dissociation stimulator (SmgGDS) plays a crucial role in the molecular mechanisms of the Rac1 signaling pathway inhibition by low-dose statins in endothelial cells.
Methods and Results: In cultured human umbilical venous endothelial cells (HUVEC), statins (atorvastatin, 10 to 30 mol/L and pitavastatin, 1 to 10 mol/L) concentration-dependently up-regulated SmgGDS and down regulated Rac1 after 24h treatment (P<0.05, n=3 each). In contrast, the Rho-kinase inhibitor, hydroxyfasudil, did not increase SmgGDS expression (n=3). The up-regulation of SmgGDS by statins was not reversed by mevalonate, farnesyl pyrophosphate or geranylgeranyl pyrophosphate (n=3 each). In SmgGDS siRNA-transfected cells, statins were no longer able to induce Rac1 degradation (P<0.01, n=3). We also examined the possible role of Rac1 degradation in mediating the anti-oxidant effects of statins. In control siRNA-transfected cells, statins decreased angiotensin II-induced endothelial production of reactive oxygen species (ROS) (P<0.01, n=8), whereas in SmgGDS siRNA-transfected cells, statins had no such inhibitory effects (n=8). The statins (atorvastatin, 10 mg/kg/day for 1 week and pravastatin, 50 mg/kg/day for 1 week) also enhanced SmgGDS expression in the mouse aorta in vivo (P<0.05, n=10). Furthermore, the protective effects of statins against angiotensin II-induced cardiovascular hypertrophy and perivascular fibrosis were noted in littermate mice in vivo (P<0.05, n=10), whereas such protective effects of statins were absent in SmgGDS-deficient mice (n=10).
Conclusions: These results indicate that statins exert their pleiotropic effects through SmgGDS up-regulation with a resultant Rac1 degradation and reduced oxidative stress in vitro and in vivo.
- © 2012 by American Heart Association, Inc.