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      Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase.

      The Journal of Biological Chemistry
      ADP Ribose Transferases, metabolism, pharmacology, Bacterial Toxins, Botulinum Toxins, Cells, Cultured, Cytosol, Cytotoxins, Endothelium, Vascular, enzymology, Escherichia coli Proteins, GTP Phosphohydrolases, genetics, GTP-Binding Proteins, Gene Expression Regulation, Enzymologic, drug effects, Guanosine 5'-O-(3-Thiotriphosphate), Guanosine Triphosphate, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Kinetics, Lipoproteins, LDL, physiology, Lovastatin, analogs & derivatives, Membrane Proteins, Mevalonic Acid, Nitric Oxide Synthase, Nitric Oxide Synthase Type III, Polyisoprenyl Phosphates, RNA Processing, Post-Transcriptional, RNA, Messenger, Sesquiterpenes, ras Proteins, rhoA GTP-Binding Protein, rhoB GTP-Binding Protein

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          Abstract

          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 microM), in the presence of L-mevalonate (200 microM), geranylgeranylpyrophosphate (GGPP, 1-10 microM), farnesylpyrophosphate (FPP, 5-10 microM), 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]GTPgammaS-binding assays revealed that mevastatin inhibited Rho membrane translocation and GTP binding activity by 60 +/- 5% and 78 +/- 6%, both of which were reversed by co-treatment with GGPP but not FPP. Furthermore, inhibition of Rho by Clostridium botulinum C3 transferase (50 microg/ml) or by overexpression of a dominant-negative N19RhoA mutant increased eNOS expression. In contrast, activation of Rho by Escherichia coli cytotoxic necrotizing factor-1 (200 ng/ml) decreased eNOS expression. These findings indicate that Rho negatively regulates eNOS expression and that HMG-CoA reductase inhibitors up-regulate eNOS expression by blocking Rho geranylgeranylation, which is necessary for its membrane-associated activity.

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