The study investigates how HMG-CoA reductase inhibitors, such as mevastatin, increase endothelial nitric oxide synthase (eNOS) expression. It shows that mevastatin increases eNOS mRNA and protein levels by 305% and 180%, respectively. This effect is reversed by co-treatment with geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate (FPP) or low-density lipoprotein (LDL). The mechanism involves Rho GTPase inhibition, as mevastatin reduces Rho membrane translocation and GTP binding activity by 60% and 78%, which are reversed by GGPP. Inhibition of Rho by Clostridium botulinum C3 transferase or overexpression of a dominant-negative RhoA mutant increases eNOS expression, while activation of Rho by Escherichia coli cytotoxic necrotizing factor-1 decreases eNOS expression. These findings indicate that Rho negatively regulates eNOS expression, and HMG-CoA reductase inhibitors up-regulate eNOS by blocking Rho geranylgeranylation, which is necessary for its membrane-associated activity. The study also shows that mevastatin increases eNOS mRNA half-life from 14 to 27 hours, which is reversed by GGPP. This suggests that mevastatin stabilizes eNOS mRNA, contributing to increased eNOS expression. Rho GTPases, including RhoA and RhoB, are essential for membrane translocation and GTP binding activity. Inhibition of Rho geranylgeranylation by mevastatin prevents Rho from translocating to the membrane, thereby reducing eNOS expression. Conversely, activation of Rho decreases eNOS expression. The study further demonstrates that Rho-mediated cytoskeletal changes may affect eNOS mRNA stability. Rho-controlled reorganization of the actin cytoskeleton may play a key role in the movement and compartmentalization of specific mRNAs, including eNOS mRNA. The findings suggest that the beneficial effects of HMG-CoA reductase inhibitors in cardiovascular diseases may not be solely due to their cholesterol-lowering effects but also due to their ability to inhibit Rho geranylgeranylation. The exact mechanism by which Rho decreases eNOS mRNA stability remains to be determined.The study investigates how HMG-CoA reductase inhibitors, such as mevastatin, increase endothelial nitric oxide synthase (eNOS) expression. It shows that mevastatin increases eNOS mRNA and protein levels by 305% and 180%, respectively. This effect is reversed by co-treatment with geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate (FPP) or low-density lipoprotein (LDL). The mechanism involves Rho GTPase inhibition, as mevastatin reduces Rho membrane translocation and GTP binding activity by 60% and 78%, which are reversed by GGPP. Inhibition of Rho by Clostridium botulinum C3 transferase or overexpression of a dominant-negative RhoA mutant increases eNOS expression, while activation of Rho by Escherichia coli cytotoxic necrotizing factor-1 decreases eNOS expression. These findings indicate that Rho negatively regulates eNOS expression, and HMG-CoA reductase inhibitors up-regulate eNOS by blocking Rho geranylgeranylation, which is necessary for its membrane-associated activity. The study also shows that mevastatin increases eNOS mRNA half-life from 14 to 27 hours, which is reversed by GGPP. This suggests that mevastatin stabilizes eNOS mRNA, contributing to increased eNOS expression. Rho GTPases, including RhoA and RhoB, are essential for membrane translocation and GTP binding activity. Inhibition of Rho geranylgeranylation by mevastatin prevents Rho from translocating to the membrane, thereby reducing eNOS expression. Conversely, activation of Rho decreases eNOS expression. The study further demonstrates that Rho-mediated cytoskeletal changes may affect eNOS mRNA stability. Rho-controlled reorganization of the actin cytoskeleton may play a key role in the movement and compartmentalization of specific mRNAs, including eNOS mRNA. The findings suggest that the beneficial effects of HMG-CoA reductase inhibitors in cardiovascular diseases may not be solely due to their cholesterol-lowering effects but also due to their ability to inhibit Rho geranylgeranylation. The exact mechanism by which Rho decreases eNOS mRNA stability remains to be determined.