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The mechanism by which 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors increase endothelial nitric oxide synthase (eNOS) expression is unknown. To determine whether changes in isoprenoid synthesis affects eNOS expression, human endothelial cells were treated with the HMG-CoA reductase inhibitor, mevastatin (1–10 μm), in the presence ofl-mevalonate (200 μm), geranylgeranylpyrophosphate (GGPP, 1–10 μm), farnesylpyrophosphate (FPP, 5–10 μm), or low density lipoprotein (LDL, 1 mg/ml). Mevastatin increased eNOS mRNA and protein levels by 305 ± 15% and 180 ± 11%, respectively. Co-treatment with l-mevalonate or GGPP, but not FPP or LDL, reversed mevastatin's effects. Because Rho GTPases undergo geranylgeranyl modification, we investigated whether Rho regulates eNOS expression. Immunoblot analyses and [³⁵S]GTPγS-binding assays revealed that mevastatin inhibited Rho …