Isoprenylation and Angiotensin II- Effects: Role of Statins

Signature Grand, Davie, Florida, USA

Background. Statins not only lower (LDL) cholesterol levels by inhibiting the HMG-CoA reductase, but also affect the isoprenoid pathway decreasing the concentration of active-isoprenylated small GTPases in the cell membrane. We previously showed that statins significantly decrease Angiotensin II (AII) stimulated ERK phosphorylation. Objectives. To investigate if statin-induced decrease in AII-stimulated ERK phosphorylation is mediated through isoprenylation pathways. Methods and Results. We studied the effects of statin treatment on AII-stimulated phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in rat aortic vascular smooth muscle cells (VSMC) in culture. These effects were evaluated in the presence or absence of geranyl geranyl pyrophosphate (GGPP) and or farnesyl diphosphate (FPP) and their inhibitors. Pretreatment with the isoprenoid inhibitors FFPI (10uM) or GGPI (10 uM) alone, did not affect the activation of ERK1/2 by AII. The combination of FFPI + GGTI significantly inhibited AII induced ERK1/2 stimulation (1.538 ± 0.16 vs. 0.649 ± 0.08, p< 0.01). Geranylation (GGPP 5 uM) or farnesylation (FPP10 uM) alone failed to inhibit simvastatin’s effect on AII stimulation of ERK1/2 but the combination of both GGPP + FPP significantly overcome simvastin’s effect (0.479 ± 0.13 vs. 1.876 ± 0.39, p < 0.05). Conclusions. These results suggest that activation of both isoprenoid pathways are involved in AII stimulation of ERK1/2 in VSMC. Furthermore, the effect of simvastatin on mitogen-activated protein kinase can be overcome by replenishing both geranylation and farnesylation pathways. The results indicate that the activity of the cholesterol biosynthetic pathway in VSMC plays an important role in vascular function.