Abstract 9653: Crucial Role of SmgGDS in the Molecular Mechanisms of the Pleiotropic Effects of HMG-CoA Reductase Inhibitors

Abstract

Background: The pleiotropic effects of HMG-CoA reductase inhibitors (statins) independent of cholesterol-lowering effects are thought to be mediated through inhibition of the Rho/Rho-kinase pathway. We have previously demonstrated that the pleiotropic effects of low-dose statins are mediated mainly through inhibition of the Rac1 signaling pathway rather than the Rho/Rho-kinase pathway. However, the molecular mechanisms of the selective inhibition of the Rac1 signaling pathway by low-dose statins remain to be elucidated. Methods and Results: We tested our hypothesis that the small GTP-binding protein dissociation stimulator (SmgGDS) plays an important role in this mechanism. In cultured human umbilical venous endothelial cells (HUVEC), statins (atorvastatin, 10 to 30 μ mol/L and pitavastatin, 1 to 10 μ mol/L) concentration-dependently increased SmgGDS expression and decreased nuclear Rac1 after 24h treatment (both P<0.05, n=3 each). Intranuclear degradation of Rac1 was reduced by the proteasome inhibitor, MG-132 (P<0.01, n=3). When SmgGDS was knockdown by its siRNA in HUVEC, statins were no longer able to induce Rac1 degradation (P<0.01, n=3) or to inhibit angiotensin II-induced production of reactive oxygen species (ROS) (P<0.01, n=8). In littermate mice, the protective effects of statins (atorvastatin, 10 mg/kg/day for 2 weeks and pravastatin, 50 mg/kg/day for 2 weeks) against AngII-induced cardiovascular hypertrophy and diastolic dysfunction were noted (AngII group vs. statin groups, P<0.01, n=10), whereas in SmgGDS-deficient mice, the protective effects of statins were absent (n=10). Finally, in normal healthy volunteers, a low-dose statin (pravastatin; 10 mg/day for 4 weeks) significantly increased SmgGDS expression (P<0.01, n=19). A significant negative correlation was noted between the extent of SmgGDS expression and oxidative stress markers (MDA-LDL-cholesterol, R=0.45; 8-OHdG, R=0.40), whereas no significant correlation was noted with total or LDL-cholesterol. Conclusions: These results provide the first direct evidence that SmgGDS plays a crucial role in the molecular mechanisms of the pleiotropic effects of statins through enhancement of intranuclear Rac1 degradation in animals and humans.