Simvastatin Modulates Angiotensin II Signaling Pathway by Preventing Rac1-Mediated Upregulation of p27

Recent experimental observations have suggested that statins may exert modulatory effects on a number of pathobiological processes beyond their cholesterol-lowering properties. Some of the pleiotropic effects of statins seem to be mediated by their ability to block the synthesis of isoprenoid intermediates, which serve as important lipid attachments re- quired for the proper function and activation of the small GTP-binding proteins. The current study explored the modu- latory effects of simvastatin (SMV) on the angiotensin II (Ang II)-induced Rac1-mediated, upregulation of cyclin-dependent kinase inhibitor p27. Ang II (100 nM) stimulation of rat mes- angial cells induced a significant increase in p27 protein ex- pression. Co-treatment of cells with SMV (1 M) inhibited Ang II-induced upregulation of p27 protein. Addition of me- valonate (200 M) or geranylgeranyl pyrophosphate (5 M) reversed the inhibitory effect of SMV on p27 protein expres- sion, suggesting that the effect of SMV is geranylgeranyl dependent. This study also provides evidence for a sequential link between Ang II stimulation and downstream activation of Rac1, intracellular H2O2 production, and Akt kinase leading to upregulation of p27 protein in mesangial cells. It was also shown that SMV, by inhibiting Rac1 activity, reversed Ang II-induced increase in intracellular H 2O2 production, Akt ac- tivation, and p27 protein expression. The data presented in this study not only elucidate Ang II-mediated signaling cascade in mesangial cells but also demonstrate for the first time the modulatory effects of SMV on Ang II-induced signaling path- way at the cell cycle level. The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, or statins, are potent inhibitors of cholesterol biosynthesis that are