Cracking Down on Caveolin: Role of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors in Modulating Edothelial Cell Nitric Oxide Production
2001; Lippincott Williams & Wilkins; Volume: 103; Issue: 1 Linguagem: Inglês
10.1161/01.cir.103.1.2
ISSN1524-4539
AutoresMichael Davis, David G. Harrison,
Tópico(s)Cholesterol and Lipid Metabolism
ResumoHomeCirculationVol. 103, No. 1Cracking Down on Caveolin: Role of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors in Modulating Edothelial Cell Nitric Oxide Production Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCracking Down on Caveolin: Role of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors in Modulating Edothelial Cell Nitric Oxide Production Michael E. Davis and David G. Harrison Michael E. DavisMichael E. Davis From the Department of Medicine, Emory University School of Medicine, and Veterans Administration Hospital, Atlanta, Ga. and David G. HarrisonDavid G. Harrison From the Department of Medicine, Emory University School of Medicine, and Veterans Administration Hospital, Atlanta, Ga. Originally published2 Jan 2001https://doi.org/10.1161/01.CIR.103.1.2Circulation. 2001;103:2–4One of the most effective approaches in the treatment of atherosclerosis has been the use of 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors (statins) to treat hypercholesterolemia. During the past decade, numerous studies involving >20 000 individuals have shown that these drugs dramatically reduce cardiovascular death, myocardial infarction, unstable angina, and stroke. Statin therapy prevents events in individuals with established cardiovascular disease and is also effective in primary prevention.1A major mechanism by which lipid lowering is thought to improve outcome is by preventing the development of new atherosclerotic lesions and by depleting lipids from established plaques (ie, plaque stabilization).23 A striking finding is that statins seem to decrease clinical events within a few months of the onset of therapy.4 This suggests that they may have beneficial effects beyond those of plaque stabilization and lesion prevention.One such beneficial effect might be the restoration of nitric oxide production by the endothelium. Endothelium-derived nitric oxide, previously known as the endothelium-derived relaxing factor, modulates vasodilatation and prevents platelet adhesion, the expression of adhesion molecules, and smooth muscle cell proliferation.5 Nitric oxide has also been shown to have antioxidant effects by enhancing the expression of superoxide dismutase,6 preventing lipid-chain reactions,7 and reacting with the superoxide anion.5 Thus, nitric oxide seems to play a major role as an endogenous protective factor against atherosclerosis. Indeed, virtually every atherosclerosis risk factor is associated with decreased endothelial cell nitric oxide production, and it is likely that this loss of nitric oxide is a major reason why these conditions predispose to vascular lesion development.Given this central role of nitric oxide in protection from atherosclerosis, several groups have become interested in the potential effects that the statins may have on its production. One recently documented effect of the statins is an upregulation of the expression of endothelial nitric oxide synthase (eNOS).89 An important and often overlooked property of the statins is that they reduce the production of both cholesterol and a number of isoprenoid intermediates. Among these are geranylgeranyl pyrophosphate (GGPP), farnesyl pyrophosphate, and isopentyl pyrophosphate.10 These molecules are not simply cholesterol precursors; they also play important roles in cell signaling. For example, GGPP and farnesyl pyrophosphate are used as lipid anchors for many membrane-associated proteins,11 and GGPP allows the small G-protein rho to attach to the cell membrane. Importantly, the activation of rho signals the destabilization of eNOS mRNA, resulting in a decrease in eNOS protein expression and, ultimately, nitric oxide production. Statins prevent this activation of rho by preventing the production of GGPP.8 Recent studies in intact animals have elegantly demonstrated that this phenomenon is responsible for the decrease in stroke size mediated by simvastatin and lovastatin.12An additional beneficial effect of the statins is to decrease endothelial cell superoxide production. Superoxide rapidly reacts with nitric oxide, leading to a loss of nitric oxide bioavailability. Recent studies by Wagner et al13 have shown that statins prevent the isoprenylation of p21 rac, a small G-protein involved in the assembly and function of the superoxide-forming NADPH oxidase.The above effects of the statins are independent of their lipid-lowering properties and have led to the concept that these agents may have benefits beyond that of cholesterol reduction. This notion is attractive, because it may explain why these drugs seem to have benefits in individuals with only modest elevations of cholesterol or early on, before plaque stabilization is likely to occur.In the current issue of Circulation, Feron et al14 illustrate another mechanism by which statins may influence endothelial cell nitric oxide production. This phenomenon relates to the fact that the activity of the eNOS enzyme is regulated by its interaction with the scaffolding protein caveolin-1. Caveolin-1 is present in high amounts in small, cholesterol-rich invaginations in the cell wall, termed caveolae, and it serves as a docking station for numerous signaling proteins.15 Among these is eNOS and, interestingly, caveolin-1 potently inhibits eNOS function by preventing its interaction with calcium/calmodulin.16 Feron et al14 make the important observation that atorvastatin dramatically inhibits caveolin-1 expression. These investigators previously showed that high levels of LDL increase caveolin-1 expression17 and, in the present study, they show an antagonistic interplay between concentrations of LDL and statins on caveolin-1 expression. In the setting of no added LDL, a tiny dose of atorvastatin (0.01 μmol/L) completely inhibited caveolin-1 expression. When endothelial cells were coincubated with LDL, the effect of atorvastatin on caveolin-1 expression was less impressive, in part due to the fact that the LDL increased the baseline levels of caveolin-1. Using coimmunoprecipitation, the investigators proceeded to show that the atorvastatin dose dependently inhibited the amount of caveolin-1 bound to eNOS. In keeping with these findings, atorvastatin also seemed to affect both the basal and stimulated release of nitric oxide.A minor concern regarding this article is that the cysteine protease inhibitor N-acetyl-leu-leu-norleucine (ALLN) was used to reduce catabolism of the sterol response element–binding protein. The problem is that ALLN may prevent the catabolism of many proteins. Thus, although ALLN was previously shown to potently inhibit caveolin-1 transcription,18 its effect in the present study may have occurred via a variety of other pathways. Nevertheless, the findings are internally consistent with the concept that sterols (in the form of LDL) stimulate the transcription of caveolin-1 and that statins inhibit this effect.Unlike the effects of statins on eNOS expression and cellular superoxide production mentioned above, the effect of atorvastatin on caveolin-1 expression is clearly dependent on its ability to lower cholesterol. Feron et al14 showed that the effect of statins on caveolin-1 could be overwhelmed by the addition of LDL. Thus, in the intact animal or human, one might expect that a similar effect on caveolin-1 expression, and a reciprocal effect on eNOS function, could be achieved by other mechanisms of cholesterol lowering, such as dietary restriction or the use of other lipid-lowering drugs. Indeed, the first study showing that cholesterol lowering improved endothelium-dependent vascular relaxation used a dietary intervention rather than statins.19 Likewise, early studies in humans also showed that cholestyramine and diet effectively improved coronary endothelium-dependent vasodilatation.20Over the past decade, there has been an enormous effort from many laboratories to understand how lipids and hypercholesterolemia alter endothelium-dependent vasodilatation using both animal models and humans. Several abnormalities of nitric oxide biosynthesis/bioavailability have been identified.5 There is substantial evidence that excessive production of superoxide or, perhaps, other free radicals can lead to inactivation of nitric oxide. Treatment of vessels and intact animals with membrane-permeable forms of superoxide dismutase corrects endothelium-dependent vasodilation in animals with experimental atherosclerosis.21 In these models, there has been ample documentation that the vascular production of superoxide is increased. In keeping with these findings, intra-arterial infusion of ascorbic acid corrects endothelium-dependent vasodilation in the forearm of hypercholesterolemic humans.22 The treatment of hypercholesterolemic humans with intravenous tetrahydrobiopterin, a critical cofactor for eNOS, has also been shown to improve endothelium-dependent vasodilation in hypercholesterolemic humans.23 Recent studies have shown that peroxynitrite potently oxidizes tetrahydrobiopterin,24 demonstrating another oxidant-based mechanism that may impair endothelium-dependent vasodilatation. Finally, in advanced human atherosclerosis, there is a clear loss of eNOS expression in endothelial cells overlying atherosclerotic lesions.25It is unclear how caveolin-1/eNOS interactions, defined in the present and previous studies by Feron et al,1417 might be involved with any of these more established mechanisms that are thought to underlie endothelial dysfunction. A major challenge for all investigators interested in this problem is to demonstrate how present and prior studies related to caveolin-1 and eNOS interactions, performed entirely in cultured cells, relate to the altered production of nitric oxide in the setting of hypercholesterolemia and atherosclerosis in vivo.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to David G. Harrison, Professor of Medicine, Emory University School of Medicine, Cardiology Department, 1639 Pierce Drive, WMB-319, Atlanta, GA 30322. E-mail [email protected] References 1 1. Ross SD, Allen IE, Connelly JE, et al. Clinical outcomes in statin treatment trials: a meta-analysis. Arch Intern Med.1999; 159:1793–1802.CrossrefMedlineGoogle Scholar2 2. Small DM, Bond MG, Waugh D, et al. Physicochemical and histological changes in the arterial wall of nonhuman primates during progression and regression of atherosclerosis. J Clin Invest.1984; 73:1590–1605.CrossrefMedlineGoogle Scholar3 3. Aikawa M, Rabkin E, Okada Y, et al. Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization. Circulation.1998; 97:2433–2444.CrossrefMedlineGoogle Scholar4 4. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study Group. N Engl J Med.1995; 333:1301–1307.CrossrefMedlineGoogle Scholar5 5. Harrison DG. Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest.1997; 100:2153–2157.CrossrefMedlineGoogle Scholar6 6. Fukai T, Siegfried MR, Ushio-Fukai M, et al. Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. J Clin Invest.2000; 105:1631–1639.CrossrefMedlineGoogle Scholar7 7. Bloodsworth A, O'Donnell VB, Freeman BA. Nitric oxide regulation of free radical- and enzyme-mediated lipid and lipoprotein oxidation. Arterioscler Thromb Vasc Biol.2000; 20:1707–1715.CrossrefMedlineGoogle Scholar8 8. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem.1998; 273:24266–24271.CrossrefMedlineGoogle Scholar9 9. Laufs U, La Fata V, Plutzky J, et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation.1998; 97:1129–1135.CrossrefMedlineGoogle Scholar10 10. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature.1990; 343:425–430.CrossrefMedlineGoogle Scholar11 11. Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem.1996; 65:241–269.CrossrefMedlineGoogle Scholar12 12. Endres M, Laufs U, Huang Z, et al. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci USA.1998; 95:8880–8885.Google Scholar13 13. Wagner AH, Kohler T, Ruckschloss U, et al. Improvement of nitric oxide–dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol.2000; 20:61–69.CrossrefMedlineGoogle Scholar14 14. Feron O, Dessy C, Desager JP, et al. HMG-CoA reductase inhibition promotes endothelial cell nitric oxide synthase activation through a decrease in caveolin abundance. Circulation.2000; 103:113–118.Google Scholar15 15. Okamoto T, Schlegel A, Scherer PE, et al. Caveolins, a family of scaffolding proteins for organizing "preassembled signaling complexes" at the plasma membrane. J Biol Chem.1998; 273:5419–5422.CrossrefMedlineGoogle Scholar16 16. Ju H, Zou R, Venema VJ, et al. Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity. J Biol Chem.1997; 272:18522–18525.CrossrefMedlineGoogle Scholar17 17. Feron O, Dessy C, Moniotte S, et al. Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase. J Clin Invest.1999; 103:897–905.CrossrefMedlineGoogle Scholar18 18. Bist A, Fielding PE, Fielding CJ. Two sterol regulatory element-like sequences mediate up-regulation of caveolin gene transcription in response to low density lipoprotein free cholesterol. Proc Natl Acad Sci USA.1997; 94:10693–10698.Google Scholar19 19. Harrison DG, Armstrong ML, Freiman PC, et al. Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis. J Clin Invest.1987; 80:1808–1811.CrossrefMedlineGoogle Scholar20 20. Leung WH, Lau CP, Wong CK. Beneficial effect of cholesterol-lowering therapy on coronary endothelium-dependent relaxation in hypercholesterolaemic patients. Lancet.1993; 341:1496–1500.CrossrefMedlineGoogle Scholar21 21. Mugge A, Elwell JH, Peterson TE, et al. Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits. Circ Res.1991; 69:1293–1300.CrossrefMedlineGoogle Scholar22 22. Ting HH, Timimi FK, Haley EA, et al. Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia. Circulation.1997; 95:2617–2622.CrossrefMedlineGoogle Scholar23 23. Stroes E, Kastelein J, Cosentino F, et al. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest.1997; 99:41–46.CrossrefMedlineGoogle Scholar24 24. Milstien S, Katusic Z. Oxidation of tetrahydrobiopterin by peroxynitrite: implications for vascular endothelial function. Biochem Biophys Res Commun.1999; 263:681–684.CrossrefMedlineGoogle Scholar25 25. Wilcox JN, Subramanian RR, Sundell CL, et al. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. 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Waters D and Hsue P (2001) What is the role of intensive cholesterol lowering in the treatment of acute coronary syndromes?, The American Journal of Cardiology, 10.1016/S0002-9149(01)01921-X, 88:7, (7-16), Online publication date: 1-Oct-2001. A. Massy Z and Guijarro C (2001) Statins: effects beyond cholesterol lowering, Nephrology Dialysis Transplantation, 10.1093/ndt/16.9.1738, 16:9, (1738-1741), Online publication date: 1-Sep-2001. January 2, 2001Vol 103, Issue 1 Advertisement Article InformationMetrics Copyright © 2001 by American Heart Associationhttps://doi.org/10.1161/01.CIR.103.1.2 Originally publishedJanuary 2, 2001 KeywordslipoproteinscholesterolEditorialsstatinsPDF download Advertisement
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