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• W2078654057 abstract "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 μm 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-1α-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. 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 μm 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-1α-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. 3-hydroxymethylglutaryl coenzyme A geranylgeranyl pyrophosphate farnesyl pyrophosphate prostaglandin thromboxane cyclooxygenase prostacyclin human aortic smooth muscle cells interleukin human immunodeficiency virus 4-morpholinepropanesulfonic acid cytotoxic necrotizing factor nitric oxide synthase The competitive inhibitors of 3-hydroxymethylglutaryl coenzyme A (HMG CoA)1 reductase, also called statins, inhibit the rate-limiting step in the synthesis of cholesterol by blocking the conversion of HMG CoA to mevalonate (1Goldstein J.L. Brown M.S. Nature. 1990; 343: 425-430Crossref PubMed Scopus (4500) Google Scholar). In this way statins are clinically useful for primary and secondary prevention of atherosclerosis (2Bellosta S. Bernini F. Ferri N. Quarato P. Canavesi M. Arnaboldi L. Fumagalli R. Paoletti R. Corsini A. Atherosclerosis. 1998; 137: S101-S109Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 3Koh K.K. Cardiovasc. Res. 2000; 47: 648-657Crossref PubMed Scopus (349) Google Scholar). However, some of their beneficial effects in therapy seem unrelated to the decrease in low density lipoprotein-cholesterol.By modulating the initial part of the cholesterol synthesis pathway, statins decrease the level of numerous important intermediate compounds including isoprenoids that contain geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP). Isoprenoids are lipid attachments involved in posttranslational modification of some proteins such as the γ subunit of the heterotrimeric G proteins, the small G proteins Ras, and Ras-like proteins such as Rho, Rap, Rab, or Ral (4Casey P.J. Curr. Opin. Cell Biol. 1994; 6: 219-225Crossref PubMed Scopus (169) Google Scholar, 5Casey P.J. Seabra M.C. J. Biol. Chem. 1996; 271: 5289-5292Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar). Statins can thus modulate various biological or physiological mechanisms.Cyclooxygenases are involved in the metabolism of arachidonic acid to prostaglandins (PGs) and thromboxane (TX) A2 (6Smith W.L. Am. J. Physiol. 1992; 263: F181-F191PubMed Google Scholar). In vascular biology, the two major products of COX are TXA2, which is mainly formed by the constitutive form of COX, COX-1 in activated platelets, and prostacyclin or PGI2, which is mainly produced in vascular cells by COX-1 and the inducible form of COX, COX-2 (7Smith W.L. Marnett L.J. DeWitt D.L. Pharmacol. Ther. 1991; 49: 153-179Crossref PubMed Scopus (386) Google Scholar, 8McAdam B.F. Catella-Lawson F. Mardini I.A. Kapoor S. Lawson J.A. FitzGerald G.A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 272-277Crossref PubMed Scopus (1182) Google Scholar). TXA2 participates in platelet aggregation and vascular contraction, whereas PGI2 acts as an anti-aggregant for platelets and a vasodilator. PGI2plays an important role in vascular physiology as illustrated by the therapeutic effect of stable analogs of PGI2 such as iloprost (9FitzGerald G.A. Charman W.N. Lancet. 1998; 351: 1206-1207Abstract Full Text Full Text PDF PubMed Google Scholar). Platelets from patients suffering from hypercholesterolemia are characterized by hypersensitivity to various aggregating agents. Notarbartolo et al. (10Notarbartolo A. Davi G. Averna M. Barbagallo C.M. Ganci A. Giammarresi C. La Placa F.P. Patrono C. Arterioscler. Thromb. Vasc. Biol. 1995; 15: 247-251Crossref PubMed Scopus (276) Google Scholar) have shown that simvastatin decreased platelet aggregation in hypercholesterolemic subjects and supported a decrease in the thromboxane platelet production, although the underlying mechanism of the statin effect on platelet function remains unclear.In this study, we demonstrated in human aortic smooth muscle cells (hASMC) that two different statins, mevastatin and lovastatin, increased COX-2 expression and PGI2 formation. We further demonstrated using selective inhibitors of geranylgeranyltransferases and modulators of Rho GTPases that geranylgeranylated proteins such as Rho seem to be responsible for COX-2 down-regulation, which is prevented by statins.DISCUSSIONWe have shown for the first time that inhibitors of HMG CoA reductase, lovastatin and mevastatin, increase the expression of COX-2 in human aortic smooth muscle cells. We confirmed the implication of the mevalonate pathway and isoprenoids in the negative modulation of the expression of COX-2 by demonstrating that the direct metabolite of HMG CoA reductase, mevalonate and the isoprenoid, GGPP, reversed the induction of COX-2 by statins and that GGTI-286, the inhibitor of geranylgeranyltransferases, induced COX-2 as for statins. Our results suggest that geranylgeranylated proteins are involved in the down-regulation of COX-2. Although COX-2 expression has been reported to implicate activation of farnesylated proteins such as Ha-Ras or Ki-Ras, farnesylation does not seem important in the present study (29Subbaramaiah K. Telang N. Ramonetti J.T. Araki R. DeVito B. Weksler B.B. Dannenberg A.J. Cancer Res. 1996; 56: 4424-4429PubMed Google Scholar, 30Sheng H. Williams C.S. Shao J. Liang P. DuBois R.N. Beauchamp R.D. J. Biol. Chem. 1998; 273: 22120-22127Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 31Heasley L.E. Thaler S. Nicks M. Price B. Skorecki K. Nemenoff R.A. J. Biol. Chem. 1997; 272: 14501-14504Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 32Fujita M. Fukui H. Kusaka T. Morita K. Fujii S. Ueda Y. Chiba T. Sakamoto C. Kawamata H. Fujimori T. J. Gastroenterol. Hepatol. 2000; 15: 1277-1281PubMed Google Scholar). On the other hand, squalene, the precursor of cholesterol, did not modify COX expression, suggesting that regulation of cellular cholesterol level is not involved in this effect. Our results are different from those reported by Inoue et al. (33Inoue I. Goto S. Mizotani K. Awata T. Mastunaga T. Kawai S. Nakajima T. Hokari S. Komoda T. Katayama S. Life Sci. 2000; 67: 863-876Crossref PubMed Scopus (307) Google Scholar) who showed that some statins reduce the level of inflammatory elements in human umbilical vein endothelial cells such as IL-1, IL-6, and COX-2. Falke et al. had also demonstrated a moderate inhibition of the release of prostacyclin in human umbilical vein endothelial cells and bovine aortic smooth muscle cells in culture (34Falke P. Mattiasson I. Stavenow L. Hood B. Pharmacol. Toxicol. 1989; 64: 173-176Crossref PubMed Scopus (35) Google Scholar). The divergence in the regulation of COX-2 expression might be cell type- and species-dependent or also related to the class of statins (33Inoue I. Goto S. Mizotani K. Awata T. Mastunaga T. Kawai S. Nakajima T. Hokari S. Komoda T. Katayama S. Life Sci. 2000; 67: 863-876Crossref PubMed Scopus (307) Google Scholar). The participation of vascular COX-2 in inflammation is still ambiguous. In our study, the increase in the expression of COX-2 might reflect either an adverse pro-inflammatory role of statins on vasculature or a positive effect if COX-2 expression in vessels were considered as beneficial in participating for instance in physiological functions or anti-inflammatory processes. Although COX-2 expression is detected in atherosclerotic plaque where it is distributed in the intima and media (35Baker C.S. Hall R.J. Evans T.J. Pomerance A. Maclouf J. Creminon C. Yacoub M.H. Polak J.M. Arterioscler. Thromb. Vasc. Biol. 1999; 19: 646-655Crossref PubMed Scopus (289) Google Scholar) and urinary prostacyclin derivatives increased in patients with atherosclerotic plaques (36FitzGerald G.A. Smith B. Pedersen A.K. Brash A.R. N. Engl. J. Med. 1984; 310: 1065-1068Crossref PubMed Scopus (394) Google Scholar), the consequence of endothelial and smooth muscle cell increase in COX-2 expression is still a matter of debate. An increase in urinary prostacyclin derivatives has been shown recently in two murine models of atherosclerosis, ApoE-deficient mice and low-density lipoprotein receptor-deficient mice on a high fat diet (37Pratico D. Cyrus T. Li H. FitzGerald G.A. Blood. 2000; 96: 3823-3826Crossref PubMed Google Scholar, 38Pratico D. Tillmann C. Zhang Z.B. Li H. FitzGerald G.A. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3358-3363Crossref PubMed Scopus (199) Google Scholar). Selective inhibition of COX-2 failed to decrease the extent of atherosclerosis in these models suggesting that COX-2, although expressed in the atherosclerotic lesions, does not participate in its progression (38Pratico D. Tillmann C. Zhang Z.B. Li H. FitzGerald G.A. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3358-3363Crossref PubMed Scopus (199) Google Scholar). Little is known about the roles of PGI2 and PGE2 on vessels. PGI2 and PGE2inhibit vascular proliferation and cell-cell interaction (39Moncada S. Gryglewski R. Bunting S. Vane J.R. Nature. 1976; 263: 663-665Crossref PubMed Scopus (2906) Google Scholar, 40Bornfeldt K.E. Campbell J.S. Koyama H. Argast G.M. Leslie C.C. Raines E.W. Krebs E.G. Ross R. J. Clin. Invest. 1997; 100: 875-885Crossref PubMed Scopus (144) Google Scholar). In normal volunteers, COX-2 contributes to the formation of PGI2 in vivo since selective inhibitors of COX-2 decreased its systemic formation (8McAdam B.F. Catella-Lawson F. Mardini I.A. Kapoor S. Lawson J.A. FitzGerald G.A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 272-277Crossref PubMed Scopus (1182) Google Scholar). Laminar shear forces have also been demonstrated to increase COX-2 expression in cultured endothelial cells (41Topper J.N. Cai J. Falb D. Gimbrone M.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 10417-10422Crossref PubMed Scopus (722) Google Scholar). As suggested recently by FitzGerald and Patrono, PGI2 may be part of a homeostatic defense mechanism limiting the consequences of platelet activation in vivo (42FitzGerald G.A. Patrono C. N. Engl. J. Med. 2001; 345: 433-442Crossref PubMed Scopus (1402) Google Scholar). Vascular PGE2 has also been reported to inhibit the expression of adhesion molecules such as ICAM-1 (43Bishop-Bailey D. Burke-Gaffney A. Hellewell P.G. Pepper J.R. Mitchell J.A. Biochem. Biophys. Res. Commun. 1998; 249: 44-47Crossref PubMed Scopus (42) Google Scholar), although this prostaglandin is considered to have pro-inflammatory effects. This suggest that COX-2-dependent release of PGE2 could have a regulatory role in limiting inflammatory responses and consequently have a protective role in cardiovascular disease (44Bishop-Bailey D. Hla T. Mitchell J.A. Int. J. Mol. Med. 1999; 3: 41-48PubMed Google Scholar). Thus, statin therapy might increase the vasodilator, anti-thrombotic, or anti-inflammatory properties of the vascular wall by increasing PGI2 and PGE2 in a COX-2-dependent manner. Whether this regulation occursin vivo following statin administration and is similarly important in all vascular beds remains to be seen.Our results are comparable with those described recently on the modulation of expression of nitric oxide synthases by statins and geranylgeranylated proteins. Laufs and Liao (45Laufs U. Liao J.K. J. Biol. Chem. 1998; 273: 24266-24271Abstract Full Text Full Text PDF PubMed Scopus (967) Google Scholar), using GGPP, reported that treatment of human endothelial cells with mevastatin increased NOS-III expression as a result of inhibition of geranylgeranylation. Finder et al. (46Finder J.D. Litz J.L. Blaskovich M.A. McGuire T.F. Qian Y. Hamilton A.D. Davies P. Sebti S.M. J. Biol. Chem. 1997; 272: 13484-13488Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar) also showed that mevastatin and GGTI-298, another GGTI similar to GGTI-286, increased NOS-II expression in rat pulmonary artery smooth muscle cells. Rho GTPases are geranylgeranylated proteins important in cell migration, contraction, cell shape, adhesion, and gene expression (23Mackay D.J. Hall A. J. Biol. Chem. 1998; 273: 20685-20688Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar, 24Bishop A.L. Hall A. Biochem. J. 2000; 348: 241-255Crossref PubMed Scopus (1661) Google Scholar). It has been shown that one of these proteins, Rho, is linked to the activation, contraction, or proliferation of vascular cells (47Seasholtz T.M. Majumdar M. Kaplan D.D. Brown J.H. Circ. Res. 1999; 84: 1186-1193Crossref PubMed Scopus (241) Google Scholar). Moreover, Rho (A or C) controls the expression of different proteins in vessels including NOS-II (48Muniyappa R. Xu R. Ram J.L. Sowers J.R. Am. J. Physiol. Heart Circ. Physiol. 2000; 278: H1762-H1768Crossref PubMed Google Scholar), NOS-III (45Laufs U. Liao J.K. J. Biol. Chem. 1998; 273: 24266-24271Abstract Full Text Full Text PDF PubMed Scopus (967) Google Scholar), TGFβ (49Park H.J. Galper J.B. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 11525-11530Crossref PubMed Scopus (61) Google Scholar), and pre-pro-endothelin-1 (ET-1) expression (50Hernandez-Perera O. Perez-Sala D. Navarro-Antolin J. Sanchez-Pascuala R. Hernandez G. Diaz C. Lamas S. J. Clin. Invest. 1998; 101: 2711-2719Crossref PubMed Scopus (745) Google Scholar, 51Hernandez-Perera O. Perez-Sala D. Soria E. Lamas S. Circ. Res. 2000; 87: 616-622Crossref PubMed Scopus (173) Google Scholar). In our system,C. difficile toxin B and CNF1, selective inhibitor and activator of all Rho GTPases, respectively, affected COX-2 expression either at the basal level or after activation by IL-1α. This suggests that Rho GTPases participate in COX-2 regulation. The further demonstration that both C. botulinum C3 transferase and Y-27632, the selective inhibitors of Rho and ROCK, respectively, induced COX-2 expression stressed the role of these proteins in the negative regulation of COX-2 expression and PGI2 formation and that these geranylgeranylated small G proteins are one of the targets of statins.Since it has been described that induction of COX-2 in some cells could participate in the apoptosis process, we tested whether statins induced apoptosis in HASMC. Although it has been described that some statins could induce apoptosis or sensitize hASMC to death receptor-induced apoptosis (52Stark W.W. Blaskovich M.A. Johnson B.A. Qian Y. Vasudevan A. Pitt B. Hamilton A.D. Sebti S.M. Davies P. Am. J. Physiol. 1998; 275: L55-L63PubMed Google Scholar, 53Knapp A. Huang J. Starling G. Kiener P. Atherosclerosis. 2000; 152: 217-227Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar), careful examination of Hoechst 33342-stained cells showed no evidence of cell death under our conditions. Observation under phase contrast, however, evidenced some morphological changes with a slight increase in rounded cells that appear to become less adherent.The effect of statins on COX-2 expression was also noted in the presence of IL-1α, a cytokine important in the atherosclerotic vascular wall and largely described to activate COX-2 (17Habib A. Creminon C. Frobert Y. Grassi J. Pradelles P. Maclouf J. J. Biol. Chem. 1993; 268: 23448-23454Abstract Full Text PDF PubMed Google Scholar, 20Jones D.A. Carlton D.P. McIntyre T.M. Zimmerman G.A. Prescott S.M. J. Biol. Chem. 1993; 268: 9049-9054Abstract Full Text PDF PubMed Google Scholar, 54Hla T. Neilson K. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 7384-7388Crossref PubMed Scopus (1478) Google Scholar). We treated cells with IL-1α first to verify the normal induction of COX-2 in hASMC as reported previously (55Bernard C. Merval R. Lebret M. Delerive P. Dusanter-Fourt I. Lehoux S. Creminon C. Staels B. Maclouf J. Tedgui A. Circ. Res. 1999; 85: 1124-1131Crossref PubMed Scopus (42) Google Scholar, 56Staels B. Koenig W. Habib A. Merval R. Lebret M. Torra I.P. Delerive P. Fadel A. Chinetti G. Fruchart J.C. Najib J. Maclouf J. Tedgui A. Nature. 1998; 393: 790-793Crossref PubMed Scopus (1051) Google Scholar) and to further check whether statins could modify COX-2 induction. We showed that these two statins increased COX-2 expression in the presence of IL-1α.The mechanism by which inhibition of Rho increases COX-2 expression is not clear. Rac1 has been shown to down-regulate Rho activation (57Sander E.E. ten Klooster J.P. van Delft S. van der Kammen R.A. Collard J.G. J. Cell Biol. 1999; 147: 1009-1022Crossref PubMed Scopus (732) Google Scholar). Signaling through IL-1 receptors implicates activation of Rac, which in turn is involved in the activation p38 MAP kinases and NF-κB, both of which are important in the regulation of COX-2 expression (23Mackay D.J. Hall A. J. Biol. Chem. 1998; 273: 20685-20688Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar, 58O. Neill L. Int. J. Clin. Lab. Res. 1995; 25: 169-177Crossref PubMed Scopus (34) Google Scholar, 59Guan Z. Buckman S.Y. Pentland A.P. Templeton D.J. Morrison A.R. J. Biol. Chem. 1998; 273: 12901-12908Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar). The balance between these two GTPases might be important in determining gene expression, i.e. COX-2. Up-regulation of COX-2 is also induced by protein kinase A activation in response to prostaglandins for example in different cell types including macrophages, vascular cells, and hepatic stellate cells (60Barry O.P. Pratico D. Lawson J.A. FitzGerald G.A. J. Clin. Invest. 1997; 99: 2118-2127Crossref PubMed Scopus (400) Google Scholar, 61Mallat A. Gallois C. Tao J. Habib A. Maclouf J. Mavier P. Preaux A.M. Lotersztajn S. J. Biol. Chem. 1998; 273: 27300-27305Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 62Wadleigh D.J. Reddy S.T. Kopp E. Ghosh S. Herschman H.R. J. Biol. Chem. 2000; 275: 6259-6266Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar). In view of the results presented here, it may be of interest that protein kinase A is known to phosphorylate and inactivate Rho A (63Lang P. Gesbert F. Delespine-Carmagnat M. Stancou R. Pouchelet M. Bertoglio J. EMBO J. 1996; 15: 510-519Crossref PubMed Scopus (479) Google Scholar) and induce COX-2 (61Mallat A. Gallois C. Tao J. Habib A. Maclouf J. Mavier P. Preaux A.M. Lotersztajn S. J. Biol. Chem. 1998; 273: 27300-27305Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 62Wadleigh D.J. Reddy S.T. Kopp E. Ghosh S. Herschman H.R. J. Biol. Chem. 2000; 275: 6259-6266Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar). Further investigation is required to understand whether or not these mechanisms are involved in the regulation of COX-2 expression by statins and if they are similar in untreated and IL-1α-stimulated cellsIn the present study, statin did not modify the half-life of the mRNA of COX-2 in IL-1α-activated cells indicating that transcriptional regulation is essentially implicated in the induction of COX-2 by statins. Our results are similar to those reported for NOS-II where regulation at the transcriptional level has been demonstrated in response to Toxin B, C3 transferases (48Muniyappa R. Xu R. Ram J.L. Sowers J.R. Am. J. Physiol. Heart Circ. Physiol. 2000; 278: H1762-H1768Crossref PubMed Google Scholar), and Y-27632 (64Chen H. Ikeda U. Shimpo M. Ikeda M. Minota S. Shimada K. Hypertension. 2000; 36: 923-928Crossref PubMed Scopus (44) Google Scholar) but different from those indicating that statins and Rho GTPase inhibitors could increase the stability of the NOS-III mRNA (45Laufs U. Liao J.K. J. Biol. Chem. 1998; 273: 24266-24271Abstract Full Text Full Text PDF PubMed Scopus (967) Google Scholar,46Finder J.D. Litz J.L. Blaskovich M.A. McGuire T.F. Qian Y. Hamilton A.D. Davies P. Sebti S.M. J. Biol. Chem. 1997; 272: 13484-13488Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Recently, Slice et al. have demonstrated in NIH 3T3 cells that Gα13 is able to increase COX-2 promoter activity through activation of Rho A (65Slice L.W. Walsh J.H. Rozengurt E. J. Biol. Chem. 1999; 274: 27562-27566Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 66Slice L.W. Bui L. Mak C. Walsh J.H. Biochem. Biophys. Res. Commun. 2000; 276: 406-410Crossref PubMed Scopus (40) Google Scholar). These data contrast with ours, which show an inhibition of COX-2 induction by Rho and Rho-associated kinases. This difference in the regulation of COX-2 might be cell-type and species dependent.We obtained increase in prostacyclin synthesis and COX-2 expression at high concentrations of lovastatin or mevastatin corresponding to 20–100 times the therapeutic doses. It seems that these concentrations are essential for the inhibition of geranylgeranylation of proteins,i.e. Rho GTPases. Previous studies have reported modification of protein expression using high concentrations of lovastatin or mevastatin in different cultured cells (45Laufs U. Liao J.K. J. Biol. Chem. 1998; 273: 24266-24271Abstract Full Text Full Text PDF PubMed Scopus (967) Google Scholar, 46Finder J.D. Litz J.L. Blaskovich M.A. McGuire T.F. Qian Y. Hamilton A.D. Davies P. Sebti S.M. J. Biol. Chem. 1997; 272: 13484-13488Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 67Laufs U. La Fata V. Plutzky J. Liao J.K. Circulation. 1998; 97: 1129-1135Crossref PubMed Scopus (1709) Google Scholar). It is noteworthy to mention that some of these reported effects,i.e. the modulation of NOS-II and NOS-III expression, were further demonstrated in vivo in mice or rats treated with statins or the Rho kinase inhibitor Y-27632 (68Laufs U. Gertz K. Huang P. Nickenig G. Bohm M. Dirnagl U. Endres M. Stroke. 2000; 31: 2442-2449Crossref PubMed Scopus (363) Google Scholar, 69Shibata R. Kai H. Seki Y. Kato S. Morimatsu M. Kaibuchi K. Imaizumi T. Circulation. 2001; 103: 284-289Crossref PubMed Scopus (121) Google Scholar). Although we are not sure that the up-regulation of COX-2 by statins we describedin vitro will occur in vivo at lower concentration of statins, it remains interesting to test whether statins or direct inhibitors of Rho or the Rho kinases such as Y-27632 can modulate in vivo the expression of COX-2.Clinical trials of statin therapy showed an improvement in cardiovascular end points, which is incompletely explained by low-density lipoprotein cholesterol modifications. Cholesterol-independent mechanisms have been suggested to explain the beneficial effect of statins beyond their effects on low density lipoprotein cholesterol (70Rosenson R.S. Tangney C.C. JAMA (J. AM. MED. ASSOC.). 1998; 279: 1643-1650Crossref PubMed Scopus (976) Google Scholar). Statins have also been reported to reduce stroke incidence (71Vaughan C.J. Delanty N. Stroke. 1999; 30: 1969-1973Crossref PubMed Scopus (353) Google Scholar). Therefore, statins could be responsible for a large favorable effect on endothelial function, plaque architecture and stability, cellular adhesion, migration and proliferation, thrombosis, and inflammation. The many in vitro and in vivodata support a role of Rho in vascular function and gene expression. Rho might be one of the potential targets of statins. Additional studies are required to understand how Rho is activated and how it regulates cellular functions under physiological conditions (72Laufs U. Liao J.K. Trends Cardiovasc. Med. 2000; 10: 143-148Crossref PubMed Scopus (160) Google Scholar,73Laufs U. Liao J.K. Circ. Res. 2000; 87: 526-528Crossref PubMed Scopus (173) Google Scholar).In summary, by preventing geranylgeranylation of some proteins including Rho, statins increase the expression of COX-2 in human vascular smooth muscle cells. Inhibition of Rho activity in vessels may be important to restore vascular function and could account for the cholesterol-unrelated effects of statins. The competitive inhibitors of 3-hydroxymethylglutaryl coenzyme A (HMG CoA)1 reductase, also called statins, inhibit the rate-limiting step in the synthesis of cholesterol by blocking the conversion of HMG CoA to mevalonate (1Goldstein J.L. Brown M.S. Nature. 1990; 343: 425-430Crossref PubMed Scopus (4500) Google Scholar). In this way statins are clinically useful for primary and secondary prevention of atherosclerosis (2Bellosta S. Bernini F. Ferri N. Quarato P. Canavesi M. Arnaboldi L. Fumagalli R. Paoletti R. Corsini A. Atherosclerosis. 1998; 137: S101-S109Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 3Koh K.K. Cardiovasc. Res. 2000; 47: 648-657Crossref PubMed Scopus (349) Google Scholar). However, some of their beneficial effects in therapy seem unrelated to the decrease in low density lipoprotein-cholesterol. By modulating the initial part of the cholesterol synthesis pathway, statins decrease the level of numerous important intermediate compounds including isoprenoids that contain geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP). Isoprenoids are lipid attachments involved in posttranslational modification of some proteins such as the γ subunit of the heterotrimeric G proteins, the small G proteins Ras, and Ras-like proteins such as Rho, Rap, Rab, or Ral (4Casey P.J. Curr. Opin. Cell Biol. 1994; 6: 219-225Crossref PubMed Scopus (169) Google Scholar, 5Casey P.J. Seabra M.C. J. Biol. Chem. 1996; 271: 5289-5292Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar). Statins can thus modulate various biological or physiological mechanisms. Cyclooxygenases are involved in the metabolism of arachidonic acid to prostaglandins (PGs) and thromboxane (TX) A2 (6Smith W.L. Am. J. Physiol. 1992; 263: F181-F191PubMed Google Scholar). In vascular biology, the two major products of COX are TXA2, which is mainly formed by the constitutive form of COX, COX-1 in activated platelets, and prostacyclin or PGI2, which is mainly produced in vascular cells by COX-1 and the inducible form of COX, COX-2 (7Smith W.L. Marnett L.J. DeWitt D.L. Pharmacol. Ther. 1991; 49: 153-179Crossref PubMed Scopus (386) Google Scholar, 8McAdam B.F. Catella-Lawson F. Mardini I.A. Kapoor S. Lawson J.A. FitzGerald G.A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 272-277Crossref PubMed Scopus (1182) Google Scholar). TXA2 participates in platelet aggregation and vascular contraction, whereas PGI2 acts as an anti-aggregant for platelets and a vasodilator. PGI2plays an important role in vascular physiology as illustrated by the therapeutic effect of stable analogs of PGI2 such as iloprost (9FitzGerald G.A. Charman W.N. Lancet. 1998; 351: 1206-1207Abstract Full Text Full Text PDF PubMed Google Scholar). Platelets from patients suffering from hypercholesterolemia are characterized by hypersensitivity to various aggregating agents. Notarbartolo et al. (10Notarbartolo A. Davi G. Averna M. Barbagallo C.M. Ganci A. Giammarresi C. La Placa F.P. Patrono C. Arterioscler. Thromb. Vasc. Biol. 1995; 15: 247-251Crossref PubMed Scopus (276) Google Scholar) have shown that simvastatin decreased platelet aggregation in hypercholesterolemic subjects and supported a decrease in the thromboxane platelet production, although the underlying mechanism of the statin effect on platelet function remains unclear. In this study, we demonstrated in human aortic smooth muscle cells (hASMC) that two different statins, meva" @default.
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• W2078654057 title "Modulation of COX-2 Expression by Statins in Human Aortic Smooth Muscle Cells" @default.
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