Importance of racl signaling pathway inhibition in the pleiotropic effects of HMG-CoA reductase inhibitors

Abstract

Background The pleiotropic effects of HMG-CoA reductase inhibitors (statins) are thought to be mediatec through inhibition of small GTP-binding proteins; however, it remains to be examined whether clinical concen trations/doses of statins actually exert them. Methods and Results In vitro studies with cultured human umbilical venous endothelial cells found that statin; (atorvastatin, pitavastatin and pravastatin at 10μmol/L) had no inhibitory effects on RhoA/Rho-kinase or Ras, buatorvastatin and pitavastatin inhibited membrane Rac1 expression. In animal studies of angiotensin II (AngII)-in fused rats, atorvastatin showed only mild inhibitory effects on AngII-induced cardiovascular hypertrophy, whereas fasudil, a selective Rho-kinase inhibitor, significantly suppressed it. Statins had no inhibitory effects on RhoA/ Rho-kinase, but inhibited both membrane and GTP-bound Rac1 in the heart, whereas fasudil only inhibited Rho kinase activity. Furthermore, the combination of atorvastatin and fasudil showed more effective inhibitory effect than fasudil alone. Finally, in studies of normal healthy volunteers, clinical doses of pravastatin or atorvastatin (20 mg/day for 1 week) significantly inhibited Racl, but not RhoA/Rho-kinase activity, in circulating leukocytes. Conclusions The pleiotropic effects of statins, if any, at their clinical doses are mediated predominantly through inhibition of the Rac1 signaling pathway.