Simvastatin and GGTI‐2133, a gernaylgeranyl transferase inhibitor, increase erythrocyte (RBC) deformability, but inhibit low oxygen tension‐induced ATP release

Abstract

Endogenous cholesterol synthesis is reduced by statin drugs that inhibit HMG‐CoA reductase. This pathway also synthesizes isoprenoids (Geranylgeranyl‐pyrophosphate and Farnesyl‐pyrophosphate), lipid molecules responsible for posttranslational modification of small GTP‐binding proteins such as Rho. Some potential effects of statins, beyond lowering blood cholesterol levels are thought to occur by inhibiting the Rho/Rho kinase pathway. We reported the Rho kinase inhibitor, Y27632, increases RBC deformability and low O2 tension‐induced ATP release from RBCs. Here we investigated the hypothesis that treatment with simvastatin or the geranylgeranyl transferase inhibitor, GGTI‐2133 would increase both RBC deformability and low O2 tension‐induced ATP release. Sprague‐Dawley rats were fed simvastatin supplemented chow (20mg/kg/day) for 30 days. RBCs obtained from rats fed statin supplemented chow were more deformable than RBCs from control rats (p< 0.05, n=6). Similar results were seen with healthy human RBCs treated with GGTI‐2133 (10 μM, p < 0.01, n=8). Statin treatment, however inhibited low O2 tension‐induced ATP release from rat RBCs (n=6) and the same result was seen after treatment with GGTI‐2133 (p<0.05, n=7). These results suggest that inhibiting geranylgeranylation impairs low O2 tension‐induced ATP release, despite increased RBC deformability. HL‐89094 and HL‐64180