This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Feron, O. Articles by Balligand, J.-L. Search for Related Content PubMed PubMed Citation Articles by Feron, O. Articles by Balligand, J.-L. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ATORVASTATIN CHOLESTEROL HEPTANOIC ACID NITRIC OXIDE PYRROLE Medline Plus Health Information Statins Related Collections Pathophysiology Cell signalling/signal transduction Lipid and lipoprotein metabolism Endothelium/vascular type/nitric oxide Mechanism of atherosclerosis/growth factors

(Circulation. 2001;103:113.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Hydroxy-Methylglutaryl–Coenzyme A Reductase Inhibition Promotes Endothelial Nitric Oxide Synthase Activation Through a Decrease in Caveolin Abundance

Olivier Feron, PhD; Chantal Dessy, PhD; Jean-Pierre Desager, PhD; J.-L. Balligand, MD, PhD

From the Department of Medicine, Unit of Pharmacology and Therapeutics, University of Louvain Medical School, Brussels, Belgium.

Correspondence to Jean-Luc Balligand, Department of Medicine, Unit of Pharmacology and Therapeutics, FATH 5349, University of Louvain Medical School, 53 Avenue Mounier, B-1200 Brussels, Belgium. E-mail balligand{at}mint.ucl.ac.be

Background—Hypercholesterolemia is causally associated with defects of endothelial nitric oxide (NO)–dependent vasodilation. Increased uptake of cholesterol by endothelial cells (ECs) upregulates the abundance of the structural protein caveolin-1 and impairs NO release through the stabilization of the inhibitory heterocomplex between caveolin-1 and endothelial NO synthase (eNOS). Therefore, we examined whether the hydroxy-methylglutaryl–coenzyme A reductase inhibitor atorvastatin modulates caveolin abundance, eNOS activity, and NO release through a reduction in endogenous cholesterol levels.

Methods and Results—ECs were incubated with increasing doses of atorvastatin in the absence or in the presence of human LDL cholesterol (LDL-Chol) fractions in the presence of antioxidants. Our results show that atorvastatin (10 nmol/L to 1 µmol/L) reduced caveolin-1 abundance in the absence (-75%) and in the presence (-20% to 70%) of LDL-Chol. This was paralleled by a decreased inhibitory interaction between caveolin-1 and eNOS and a restoration and/or potentiation of the basal (+45%) and agonist-stimulated (+107%) eNOS activity. These effects were observed in the absence of changes in eNOS abundance and were reversed with mevalonate. In the presence of LDL-Chol, atorvastatin also promoted the agonist-induced association of eNOS and the chaperone Hsp90, resulting in the potentiation of eNOS activation.

Conclusions—We provide biochemical and functional evidence that atorvastatin promotes NO production by decreasing caveolin-1 expression in ECs, regardless of the level of extracellular LDL-Chol. These findings highlight the therapeutic potential of inhibiting cholesterol synthesis in peripheral cells to correct NO-dependent endothelial dysfunction associated with hypercholesterolemia and possibly other diseases.

Key Words: cholesterol • nitric oxide • endothelium • atorvastatin

This article has been cited by other articles:

				T. Khan, M. P. Hamilton, D. I. Mundy, S. C. Chua, and P. E. Scherer Impact of Simvastatin on Adipose Tissue: Pleiotropic Effects in Vivo Endocrinology, December 1, 2009; 150(12): 5262 - 5272. [Abstract] [Full Text] [PDF]

				J. Igarashi, K. Shoji, T. Hashimoto, T. Moriue, K. Yoneda, T. Takamura, T. Yamashita, Y. Kubota, and H. Kosaka Transforming growth factor-{beta}1 downregulates caveolin-1 expression and enhances sphingosine 1-phosphate signaling in cultured vascular endothelial cells Am J Physiol Cell Physiol, November 1, 2009; 297(5): C1263 - C1274. [Abstract] [Full Text] [PDF]

				F. Ali, M. Zakkar, K. Karu, E. A. Lidington, S. S. Hamdulay, J. J. Boyle, M. Zloh, A. Bauer, D. O. Haskard, P. C. Evans, et al. Induction of the Cytoprotective Enzyme Heme Oxygenase-1 by Statins Is Enhanced in Vascular Endothelium Exposed to Laminar Shear Stress and Impaired by Disturbed Flow J. Biol. Chem., July 10, 2009; 284(28): 18882 - 18892. [Abstract] [Full Text] [PDF]

				Y. Birnbaum, Y. Lin, Y. Ye, R. Merla, J. R. Perez-Polo, and B. F. Uretsky Pretreatment With High-Dose Statin, But Not Low-Dose Statin, Ezetimibe, or the Combination of Low-Dose Statin and Ezetimibe, Limits Infarct Size in the Rat Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2008; 13(1): 72 - 79. [Abstract] [PDF]

				J. A. Joles Statins and small GTPases: Koch's postulates and chronic kidney disease Nephrol. Dial. Transplant., February 1, 2008; 23(2): 433 - 438. [Full Text] [PDF]

				F. Desjardins, B. Sekkali, W. Verreth, M. Pelat, D. De Keyzer, A. Mertens, G. Smith, M.-C. Herregods, P. Holvoet, and J.-L. Balligand Rosuvastatin increases vascular endothelial PPAR{gamma} expression and corrects blood pressure variability in obese dyslipidaemic mice Eur. Heart J., January 1, 2008; 29(1): 128 - 137. [Abstract] [Full Text] [PDF]

				B. Fibbi, A. Morelli, M. Marini, X.-H. Zhang, R. Mancina, L. Vignozzi, S. Filippi, A. Chavalmane, E. Silvestrini, E. Colli, et al. Atorvastatin But Not Elocalcitol Increases Sildenafil Responsiveness in Spontaneously Hypertensive Rats by Regulating the RhoA/ROCK Pathway J Androl, January 1, 2008; 29(1): 70 - 84. [Abstract] [Full Text] [PDF]

				S. Mangat, S. Agarwal, and C. Rosendorff Do Statins Lower Blood Pressure? Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2007; 12(2): 112 - 123. [Abstract] [PDF]

				C H Strey, J M Young, J H Lainchbury, C M Frampton, M G Nicholls, A M Richards, and R S Scott Short-term statin treatment improves endothelial function and neurohormonal imbalance in normocholesterolaemic patients with non-ischaemic heart failure Heart, November 1, 2006; 92(11): 1603 - 1609. [Abstract] [Full Text] [PDF]

				W.-W. Lin, Y.-C. Lin, T.-Y. Chang, S.-H. Tsai, H.-C. Ho, Y.-T. Chen, and V. C. Yang Caveolin-1 Expression Is Associated with Plaque Formation in Hypercholesterolemic Rabbits J. Histochem. Cytochem., August 1, 2006; 54(8): 897 - 904. [Abstract] [Full Text] [PDF]

				S. Batova, J. DeWever, T. Godfraind, J.-L. Balligand, C. Dessy, and O. Feron The calcium channel blocker amlodipine promotes the unclamping of eNOS from caveolin in endothelial cells Cardiovasc Res, August 1, 2006; 71(3): 478 - 485. [Abstract] [Full Text] [PDF]

				Z. Yang and X.-F. Ming Recent advances in understanding endothelial dysfunction in atherosclerosis. Clin. Med. Res., March 1, 2006; 4(1): 53 - 65. [Abstract] [Full Text] [PDF]

				B. Erdos, J. A. Snipes, C. D. Tulbert, P. Katakam, A. W. Miller, and D. W. Busija Rosuvastatin improves cerebrovascular function in Zucker obese rats by inhibiting NAD(P)H oxidase-dependent superoxide production Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1264 - H1270. [Abstract] [Full Text] [PDF]

				O. Feron and J.-L. Balligand Caveolins and the regulation of endothelial nitric oxide synthase in the heart Cardiovasc Res, March 1, 2006; 69(4): 788 - 797. [Abstract] [Full Text] [PDF]

				A. Zulli, B. F. Buxton, M. J. Black, Z. Ming, A. Cameron, and D. L. Hare The Immunoquantification of Caveolin-1 and eNOS in Human and Rabbit Diseased Blood Vessels J. Histochem. Cytochem., February 1, 2006; 54(2): 151 - 159. [Abstract] [Full Text] [PDF]

				M Egred, G Viswanathan, and G K Davis Myocardial infarction in young adults Postgrad. Med. J., December 1, 2005; 81(962): 741 - 745. [Abstract] [Full Text] [PDF]

				A. G. Herman and S. Moncada Therapeutic potential of nitric oxide donors in the prevention and treatment of atherosclerosis Eur. Heart J., October 1, 2005; 26(19): 1945 - 1955. [Abstract] [Full Text] [PDF]

				U. Landmesser, F. Bahlmann, M. Mueller, S. Spiekermann, N. Kirchhoff, S. Schulz, C. Manes, D. Fischer, K. de Groot, D. Fliser, et al. Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans Circulation, May 10, 2005; 111(18): 2356 - 2363. [Abstract] [Full Text] [PDF]

				C. L. Wainwright Statins-is there no end to their usefulness? Cardiovasc Res, February 1, 2005; 65(2): 296 - 298. [Full Text] [PDF]

				M. P. McGowan and for the Treating to New Target Study Group There Is No Evidence for an Increase in Acute Coronary Syndromes After Short-Term Abrupt Discontinuation of Statins in Stable Cardiac Patients Circulation, October 19, 2004; 110(16): 2333 - 2335. [Abstract] [Full Text] [PDF]

				U. Landmesser, N. Engberding, F. H. Bahlmann, A. Schaefer, A. Wiencke, A. Heineke, S. Spiekermann, D. Hilfiker-Kleiner, C. Templin, D. Kotlarz, et al. Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase Circulation, October 5, 2004; 110(14): 1933 - 1939. [Abstract] [Full Text] [PDF]

				J. A. Beckman, J. K. Liao, S. Hurley, L. A. Garrett, D. Chui, D. Mitra, and M. A. Creager Atorvastatin Restores Endothelial Function in Normocholesterolemic Smokers Independent of Changes in Low-Density Lipoprotein Circ. Res., July 23, 2004; 95(2): 217 - 223. [Abstract] [Full Text] [PDF]

				D.D. Waters and K.K. Khush Management of the acute coronary syndrome patient Eur. Heart J. Suppl., July 1, 2004; 6(suppl_C): C49 - C57. [Abstract] [Full Text] [PDF]

				J. Davignon and P. Ganz Role of Endothelial Dysfunction in Atherosclerosis Circulation, June 15, 2004; 109(23_suppl_1): III-27 - III-32. [Abstract] [Full Text]

				J. Davignon Beneficial Cardiovascular Pleiotropic Effects of Statins Circulation, June 15, 2004; 109(23_suppl_1): III-39 - III-43. [Abstract] [Full Text]

				J.-P. Gratton, P. Bernatchez, and W. C. Sessa Caveolae and Caveolins in the Cardiovascular System Circ. Res., June 11, 2004; 94(11): 1408 - 1417. [Abstract] [Full Text] [PDF]

				S. Kawashima and M. Yokoyama Dysfunction of Endothelial Nitric Oxide Synthase and Atherosclerosis Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 998 - 1005. [Abstract] [Full Text] [PDF]

				R. P. Mason, M. F. Walter, and R. F. Jacob Effects of HMG-CoA Reductase Inhibitors on Endothelial Function: Role of Microdomains and Oxidative Stress Circulation, June 1, 2004; 109(21_suppl_1): II-34 - II-41. [Abstract] [Full Text] [PDF]

				C. R. Wolfram Kuhlmann, C. Gast, F. Li, M. Schafer, H. Tillmanns, B. Waldecker, and J. Wiecha Cerivastatin Activates Endothelial Calcium-Activated Potassium Channels and Thereby Modulates Endothelial Nitric Oxide Production and Cell Proliferation J. Am. Soc. Nephrol., April 1, 2004; 15(4): 868 - 875. [Abstract] [Full Text] [PDF]

				M. S. Goligorsky and W. Wang Statins' Coat of Many Colors Receives Yet Another Hue J. Am. Soc. Nephrol., April 1, 2004; 15(4): 1098 - 1100. [Full Text] [PDF]

				G. A.M. Plenz, O. Hofnagel, H. Robenek, M. Pelat, C. Dessy, P. Massion, J.-P. Desager, O. Feron, and J.-L. Balligand Differential Modulation of Caveolin-1 Expression in Cells of the Vasculature by Statins * Response Circulation, January 20, 2004; 109 (2): e7 - e8. [Full Text] [PDF]

				R. E. Girgis, D. Li, X. Zhan, J. G. N. Garcia, R. M. Tuder, P. M. Hassoun, and R. A. Johns Attenuation of chronic hypoxic pulmonary hypertension by simvastatin Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H938 - H945. [Abstract] [Full Text] [PDF]

				B. C. Kone, T. Kuncewicz, W. Zhang, and Z.-Y. Yu Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide Am J Physiol Renal Physiol, August 1, 2003; 285(2): F178 - F190. [Abstract] [Full Text] [PDF]

				M. Pelat, C. Dessy, P. Massion, J.-P. Desager, O. Feron, and J.-L. Balligand Rosuvastatin Decreases Caveolin-1 and Improves Nitric Oxide-Dependent Heart Rate and Blood Pressure Variability in Apolipoprotein E-/- Mice In Vivo Circulation, May 20, 2003; 107(19): 2480 - 2486. [Abstract] [Full Text] [PDF]

				R. P. Mason and R. F. Jacob Membrane Microdomains and Vascular Biology: Emerging Role in Atherogenesis Circulation, May 6, 2003; 107(17): 2270 - 2273. [Full Text] [PDF]

				Z. Ou, J. Ou, A. W. Ackerman, K. T. Oldham, and K. A. Pritchard Jr L-4F, an Apolipoprotein A-1 Mimetic, Restores Nitric Oxide and Superoxide Anion Balance in Low-Density Lipoprotein-Treated Endothelial Cells Circulation, March 25, 2003; 107(11): 1520 - 1524. [Abstract] [Full Text] [PDF]

				P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF]

				M. Gervais, S. Pons, A. Nicoletti, C. Cosson, J.-F. Giudicelli, and C. Richer Fluvastatin Prevents Renal Dysfunction and Vascular NO Deficit in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 183 - 189. [Abstract] [Full Text] [PDF]

				P. Ratajczak, T. Damy, C. Heymes, P. Oliviero, F. Marotte, E. Robidel, R. Sercombe, J. Boczkowski, L. Rappaport, and J.-L. Samuel Caveolin-1 and -3 dissociations from caveolae to cytosol in the heart during aging and after myocardial infarction in rat Cardiovasc Res, February 1, 2003; 57(2): 358 - 369. [Abstract] [Full Text] [PDF]

				A. Piech, C. Dessy, X. Havaux, O. Feron, and J.-L. Balligand Differential regulation of nitric oxide synthases and their allosteric regulators in heart and vessels of hypertensive rats Cardiovasc Res, February 1, 2003; 57(2): 456 - 467. [Abstract] [Full Text] [PDF]

				I. L Williams, A. Vazir, and A. G Zaman Review: The management of stable angina in diabetes The British Journal of Diabetes & Vascular Disease, January 1, 2003; 3(1): 18 - 25. [Abstract] [PDF]

				P B Massion and J-L Balligand Modulation of cardiac contraction, relaxation and rate by the endothelial nitric oxide synthase (eNOS): lessons from genetically modified mice J. Physiol., January 1, 2003; 546(1): 63 - 75. [Abstract] [Full Text] [PDF]

				A. Skaletz-Rorowski, M. Lutchman, Y. Kureishi, D. J. Lefer, J. R. Faust, and K. Walsh HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells Cardiovasc Res, January 1, 2003; 57(1): 253 - 264. [Abstract] [Full Text] [PDF]

				C. Indolfi, D. Torella, C. Coppola, A. Curcio, F. Rodriguez, A. Bilancio, A. Leccia, O. Arcucci, M. Falco, D. Leosco, et al. Physical Training Increases eNOS Vascular Expression and Activity and Reduces Restenosis After Balloon Angioplasty or Arterial Stenting in Rats Circ. Res., December 13, 2002; 91(12): 1190 - 1197. [Abstract] [Full Text] [PDF]

				R. van Haperen, M. de Waard, E. van Deel, B. Mees, M. Kutryk, T. van Aken, J. Hamming, F. Grosveld, D. J. Duncker, and R. de Crom Reduction of Blood Pressure, Plasma Cholesterol, and Atherosclerosis by Elevated Endothelial Nitric Oxide J. Biol. Chem., December 6, 2002; 277(50): 48803 - 48807. [Abstract] [Full Text] [PDF]

				Y.-Y. Zhao, Y. Liu, R.-V. Stan, L. Fan, Y. Gu, N. Dalton, P.-H. Chu, K. Peterson, J. Ross Jr., and K. R. Chien Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice PNAS, August 20, 2002; 99(17): 11375 - 11380. [Abstract] [Full Text] [PDF]

				A. Ichihara, M. Hayashi, M. Ryuzaki, M. Handa, T. Furukawa, and T. Saruta Fluvastatin prevents development of arterial stiffness in haemodialysis patients with type 2 diabetes mellitus Nephrol. Dial. Transplant., August 1, 2002; 17(8): 1513 - 1517. [Abstract] [Full Text] [PDF]

				M. A. Sardo, M. Castaldo, M. Cinquegrani, M. Bonaiuto, A. Maesano, A. Versace, M. Spadaro, S. Campo, G. Nicocia, D. Altavilla, et al. Effects of Atorvastatin Treatment on sICAM-1 and Plasma Nitric Oxide Levels in Hypercholesterolemic Subjects Clinical and Applied Thrombosis/Hemostasis, July 1, 2002; 8(3): 257 - 263. [Abstract] [PDF]

				S. Homma, R. L. Sacco, M. R. Di Tullio, R. R. Sciacca, J.P. Mohr, and for the PFO in Cryptogenic Stroke Study (PICSS) In Effect of Medical Treatment in Stroke Patients With Patent Foramen Ovale: Patent Foramen Ovale in Cryptogenic Stroke Study Circulation, June 4, 2002; 105(22): 2625 - 2631. [Abstract] [Full Text] [PDF]

				J.-L. Balligand Heat Shock Protein 90 in Endothelial Nitric Oxide Synthase Signaling: Following the Lead(er)? Circ. Res., May 3, 2002; 90(8): 838 - 841. [Full Text] [PDF]

				J. Fontana, D. Fulton, Y. Chen, T. A. Fairchild, T. J. McCabe, N. Fujita, T. Tsuruo, and W. C. Sessa Domain Mapping Studies Reveal That the M Domain of hsp90 Serves as a Molecular Scaffold to Regulate Akt-Dependent Phosphorylation of Endothelial Nitric Oxide Synthase and NO Release Circ. Res., May 3, 2002; 90(8): 866 - 873. [Abstract] [Full Text] [PDF]

				S. I. McFarlane, R. Muniyappa, R. Francisco, and J. R. Sowers Pleiotropic Effects of Statins: Lipid Reduction and Beyond J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1451 - 1458. [Abstract] [Full Text] [PDF]

				R. Dechend, D. Muller, J. K. Park, A. Fiebeler, H. Haller, and F. C. Luft Statins and angiotensin II-induced vascular injury Nephrol. Dial. Transplant., March 1, 2002; 17(3): 349 - 353. [Full Text] [PDF]

				R. A. Santizo, H.-L. Xu, E. Galea, S. Muyskens, V. L. Baughman, and D. A. Pelligrino Combined Endothelial Nitric Oxide Synthase Upregulation and Caveolin-1 Downregulation Decrease Leukocyte Adhesion in Pial Venules of Ovariectomized Female Rats Stroke, February 1, 2002; 33(2): 613 - 616. [Abstract] [Full Text] [PDF]

				G. Nickenig and D. G. Harrison The AT1-Type Angiotensin Receptor in Oxidative Stress and Atherogenesis: Part II: AT1 Receptor Regulation Circulation, January 29, 2002; 105(4): 530 - 536. [Full Text] [PDF]

				A. Piech, P. E. Massart, C. Dessy, O. Feron, X. Havaux, N. Morel, J.-L. Vanoverschelde, J. Donckier, and J.-L. Balligand Decreased expression of myocardial eNOS and caveolin in dogs with hypertrophic cardiomyopathy Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H219 - H231. [Abstract] [Full Text] [PDF]

				T. O. Cheng, M. Egred, J.C. Patel, and S. Walton Management of Paradoxical Coronary Embolism Circulation, December 11, 2001; 104 (24): e153 - e153. [Full Text] [PDF]

				C. Knauf, S. Ferreira, M. Hamdane, C. Mailliot, V. Prevot, J.-C. Beauvillain, and D. Croix Variation of Endothelial Nitric Oxide Synthase Synthesis in the Median Eminence during the Rat Estrous Cycle: An Additional Argument for the Implication of Vascular Blood Vessel in the Control of GnRH Release Endocrinology, October 1, 2001; 142(10): 4288 - 4294. [Abstract] [Full Text] [PDF]

				D.Y Li, H.J Chen, and J.L Mehta Statins inhibit oxidized-LDL-mediated LOX-1 expression, uptake of oxidized-LDL and reduction in PKB phosphorylation Cardiovasc Res, October 1, 2001; 52(1): 130 - 135. [Abstract] [Full Text] [PDF]

				J. M. STULAK, A. LERMAN, M. R. PORCEL, J. A. CACCITOLO, J. C. ROMERO, H. V. SCHAFF, C. NAPOLI, and L. O. LERMAN Renal Vascular Function in Hypercholesterolemia Is Preserved by Chronic Antioxidant Supplementation J. Am. Soc. Nephrol., September 1, 2001; 12(9): 1882 - 1891. [Abstract] [Full Text] [PDF]

				M. E. Davis and D. G. Harrison Cracking Down on Caveolin: Role of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors in Modulating Edothelial Cell Nitric Oxide Production Circulation, January 2, 2001; 103(1): 2 - 4. [Full Text] [PDF]

				A. Brouet, P. Sonveaux, C. Dessy, S. Moniotte, J.-L. Balligand, and O. Feron Hsp90 and Caveolin Are Key Targets for the Proangiogenic Nitric Oxide-Mediated Effects of Statins Circ. Res., November 9, 2001; 89(10): 866 - 873. [Abstract] [Full Text] [PDF]

				J. Fontana, D. Fulton, Y. Chen, T. A. Fairchild, T. J. McCabe, N. Fujita, T. Tsuruo, and W. C. Sessa Domain Mapping Studies Reveal That the M Domain of hsp90 Serves as a Molecular Scaffold to Regulate Akt-Dependent Phosphorylation of Endothelial Nitric Oxide Synthase and NO Release Circ. Res., May 3, 2002; 90(8): 866 - 873. [Abstract] [Full Text] [PDF]