Modulation of COX-2 expression by statins in human aortic smooth muscle cells. Involvement of geranylgeranylated proteins.
Cyclooxygenase (COX)-2 and COX-1 play an important role in prostacyclin production in vessels and participate in maintaining vascular homeostasis. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, which is crucial in cholesterol biosynthesis. Recently, cholesterol-independent effects of statins have been described. In this study, we evaluated the effect of two inhibitors of HMG CoA reductase, mevastatin and lovastatin, on the production of prostacyclin and the expression of COX in human aortic smooth muscle cells. Treatment of cells with 25 microm mevastatin or lovastatin resulted in the induction of COX-2 and increase in prostacyclin production. Mevalonate, the direct metabolite of HMG CoA reductase, and geranylgeranyl-pyrophosphate reversed this effect. GGTI-286, a selective inhibitor of geranylgeranyltransferases, increased COX-2 expression and prostacyclin formation, thus indicating the involvement of geranylgeranylated proteins in the down-regulation of COX-2. Furthermore, Clostridium difficile toxin B, an inhibitor of the Rho GTP-binding protein family, the Rho selective inhibitor C3 transferase, and Y-27632, a selective inhibitor of the Rho-associated kinases, targets of Rho A, increased COX-2 expression whereas the activator of the Rho GTPase, the cytotoxic necrotizing factor 1, blocked interlukin-1alpha-dependent COX-2 induction. These results demonstrate that statins up-regulate COX-2 expression and subsequent prostacyclin formation in human aortic smooth muscle cells in part through inhibition of Rho.
Degraeve
F
F
Commissariat à l'Energie Atomique (CEA), Service de Pharmacologie et d'Immunologie, 91191 Gif sur Yvette, France.
Bolla
M
M
Blaie
S
S
Créminon
C
C
Quéré
I
I
Boquet
P
P
Lévy-Toledano
S
S
Bertoglio
J
J
Habib
A
A
D000577:Amides / Q000494:pharmacology; D001011:Aorta / Q000201:enzymology* / Q000378:metabolism; D017209:Apoptosis; D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D018076:DNA, Complementary / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007375:Interleukin-1 / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis*; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008565:Membrane Proteins; D008798:Mevalonic Acid / Q000737:chemistry / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology* / Q000201:enzymology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D017368:Protein Prenylation; D011725:Pyridines / Q000494:pharmacology; D013997:Time Factors; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000577:Amides; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; C437105:GGTI 286; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011725:Pyridines; C031815:toxB protein, Clostridium difficile; C108830:Y 27632; D003609:Dactinomycin; C012258:mevastatin; D008148:Lovastatin; D011464:Epoprostenol; D006903:Hydroxymethylglutaryl CoA Reductases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020741:rho GTP-Binding Proteins; D007930:Leucine; D008798:Mevalonic Acid