Importance of Rac1 Signaling Pathway Inhibition in the Pleiotropic Effects of HMG-CoA Reductase Inhibitors

Abstract

The pleiotropic effects of HMG-CoA reductase inhibitors (statins) are thought to be mediated through inhibition of small GTP-binding proteins; however, it remains to be examined whether clinical concentrations/doses of statins actually exert them. In vitro studies with cultured human umbilical venous endothelial cells found that statins (atorvastatin, pitavastatin and pravastatin at 10 micromol/L) had no inhibitory effects on RhoA/Rho-kinase or Ras, but atorvastatin and pitavastatin inhibited membrane Rac1 expression. In animal studies of angiotensin II (AngII)-infused 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 effects than fasudil alone. Finally, in studies of normal healthy volunteers, clinical doses of pravastatin or atorvastatin (20 mg/day for 1 week) significantly inhibited Rac1, but not RhoA/Rho-kinase activity, in circulating leukocytes. The pleiotropic effects of statins, if any, at their clinical doses are mediated predominantly through inhibition of the Rac1 signaling pathway.