Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1712-1719
doi: 10.1161/hq1101.098486
doi: 10.1161/hq1101.098486
© 2001 American Heart Association, Inc.
Brief Review |
Pleiotropic Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors
From the Cardiovascular Division, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, Mass.
Correspondence to Dr James K. Liao, Brigham & Women’s Hospital, 221 Longwood Ave, LMRC-322, Boston, MA 02115. E-mail jliao{at}rics.bwh.harvard.edu
Abstract—— The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins are potent inhibitors of cholesterol biosynthesis. Several large clinical trials have demonstrated the beneficial effects of statins in the primary and secondary prevention of coronary heart disease. However, the overall clinical benefits observed with statin therapy appear to be greater than what might be expected from changes in lipid profile alone, suggesting that the beneficial effects of statins may extend beyond their effects on serum cholesterol levels. Indeed, recent experimental and clinical evidence indicates that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, and decreasing oxidative stress and vascular inflammation. Many of these pleiotropic effects of statins are mediated by their ability to block the synthesis of important isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signaling molecules. In particular, the inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the direct cellular effects of statins on the vascular wall.
Key Words: endothelium • vascular smooth muscle • platelets • atherosclerosis • inflammation
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H. Shimokawa and A. Takeshita Rho-Kinase Is an Important Therapeutic Target in Cardiovascular Medicine Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1767 - 1775. [Abstract] [Full Text] [PDF]
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A. Jula, J. Marniemi, T. Ronnemaa, A. Virtanen, and R. Huupponen Effects of Diet and Simvastatin on Fatty Acid Composition in Hypercholesterolemic Men: A Randomized Controlled Trial Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1952 - 1959. [Abstract] [Full Text] [PDF]
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 J. Shannon, S. Tewoderos, M. Garzotto, T. M. Beer, R. Derenick, A. Palma, and P. E. Farris Statins and Prostate Cancer Risk: A Case-Control Study Am. J. Epidemiol., August 15, 2005; 162(4): 318 - 325. [Abstract] [Full Text] [PDF]
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M.-Y. Tseng, M. Czosnyka, H. Richards, J. D. Pickard, and P. J. Kirkpatrick Effects of Acute Treatment With Pravastatin on Cerebral Vasospasm, Autoregulation, and Delayed Ischemic Deficits After Aneurysmal Subarachnoid Hemorrhage: A Phase II Randomized Placebo-Controlled Trial Stroke, August 1, 2005; 36(8): 1627 - 1632. [Abstract] [Full Text] [PDF]
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R. Corti, V. Fuster, Z. A. Fayad, S. G. Worthley, G. Helft, W. F. Chaplin, J. Muntwyler, J. F. Viles-Gonzalez, J. Weinberger, D. A. Smith, et al. Effects of Aggressive Versus Conventional Lipid-Lowering Therapy by Simvastatin on Human Atherosclerotic Lesions: A Prospective, Randomized, Double-Blind Trial With High-Resolution Magnetic Resonance Imaging J. Am. Coll. Cardiol., July 5, 2005; 46(1): 106 - 112. [Abstract] [Full Text] [PDF]
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H. Methe, J.-O. Kim, S. Kofler, M. Nabauer, and M. Weis Statins Decrease Toll-Like Receptor 4 Expression and Downstream Signaling in Human CD14+ Monocytes Arterioscler. Thromb. Vasc. Biol., July 1, 2005; 25(7): 1439 - 1445. [Abstract] [Full Text] [PDF]
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C. A. Argmann, J. Y. Edwards, C. G. Sawyez, C. H. O'Neil, R. A. Hegele, J. G. Pickering, and M. W. Huff Regulation of Macrophage Cholesterol Efflux through Hydroxymethylglutaryl-CoA Reductase Inhibition: A ROLE FOR RhoA IN ABCA1-MEDIATED CHOLESTEROL EFFLUX J. Biol. Chem., June 10, 2005; 280(23): 22212 - 22221. [Abstract] [Full Text] [PDF]
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M. Yamakuchi, J. J.M. Greer, S. J. Cameron, K. Matsushita, C. N. Morrell, K. Talbot-Fox, W. M. Baldwin III, D. J. Lefer, and C. J. Lowenstein HMG-CoA Reductase Inhibitors Inhibit Endothelial Exocytosis and Decrease Myocardial Infarct Size Circ. Res., June 10, 2005; 96(11): 1185 - 1192. [Abstract] [Full Text] [PDF]
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H. Lorenz, C. Junger, K. Seidl, A. Gitt, S. Schneider, R. Schiele, H. Wienbergen, R. Winkler, M. Gottwik, W. Delius, et al. Do statins influence the prognostic impact of non-sustained ventricular tachycardia after ST-elevation myocardial infarction? Eur. Heart J., June 1, 2005; 26(11): 1078 - 1085. [Abstract] [Full Text] [PDF]
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R. Sugano, H. Matsuoka, N. Haramaki, H. Umei, E. Murase, K. Fukami, S. Iida, H. Ikeda, and T. Imaizumi Polymorphonuclear Leukocytes May Impair Endothelial Function: Results of Crossover Randomized Study of Lipid-Lowering Therapies Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1262 - 1267. [Abstract] [Full Text] [PDF]
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L. H. Smith, M. S. Petrie, J. D. Morrow, J. A. Oates, and D. E. Vaughan The sterol response element binding protein regulates cyclooxygenase-2 gene expression in endothelial cells J. Lipid Res., May 1, 2005; 46(5): 862 - 871. [Abstract] [Full Text] [PDF]
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Y. Urano, I. Hayashi, N. Isoo, P. C. Reid, Y. Shibasaki, N. Noguchi, T. Tomita, T. Iwatsubo, T. Hamakubo, and T. Kodama Association of active {gamma}-secretase complex with lipid rafts J. Lipid Res., May 1, 2005; 46(5): 904 - 912. [Abstract] [Full Text] [PDF]
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A. G. Olsson, G. G. Schwartz, M. Szarek, W. J. Sasiela, M. D. Ezekowitz, P. Ganz, M. F. Oliver, D. Waters, and A. Zeiher High-density lipoprotein, but not low-density lipoprotein cholesterol levels influence short-term prognosis after acute coronary syndrome: results from the MIRACL trial Eur. Heart J., May 1, 2005; 26(9): 890 - 896. [Abstract] [Full Text] [PDF]
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S. J. Zieman, V. Melenovsky, and D. A. Kass Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 932 - 943. [Abstract] [Full Text] [PDF]
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A. Schafer, D. Fraccarollo, M. Eigenthaler, P. Tas, A. Firnschild, S. Frantz, G. Ertl, and J. Bauersachs Rosuvastatin Reduces Platelet Activation in Heart Failure: Role of NO Bioavailability Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 1071 - 1077. [Abstract] [Full Text] [PDF]
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 G. K. Hansson Inflammation, Atherosclerosis, and Coronary Artery Disease N. Engl. J. Med., April 21, 2005; 352(16): 1685 - 1695. [Full Text] [PDF]
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R. Madonna, P. Di Napoli, M. Massaro, A. Grilli, M. Felaco, A. De Caterina, D. Tang, R. De Caterina, and Y.-J. Geng Simvastatin Attenuates Expression of Cytokine-inducible Nitric-oxide Synthase in Embryonic Cardiac Myoblasts J. Biol. Chem., April 8, 2005; 280(14): 13503 - 13511. [Abstract] [Full Text] [PDF]
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L. Sironi, E. Gianazza, P. Gelosa, U. Guerrini, E. Nobili, A. Gianella, B. Cremonesi, R. Paoletti, and E. Tremoli Rosuvastatin, but not Simvastatin, Provides End-Organ Protection in Stroke-Prone Rats by Antiinflammatory Effects Arterioscler. Thromb. Vasc. Biol., March 1, 2005; 25(3): 598 - 603. [Abstract] [Full Text] [PDF]
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M. Fu, J. Zhang, Y.-H. Tseng, T. Cui, X. Zhu, Y. Xiao, Y. Mou, H. De Leon, M. M.J. Chang, Y. Hamamori, et al. Rad GTPase Attenuates Vascular Lesion Formation by Inhibition of Vascular Smooth Muscle Cell Migration Circulation, March 1, 2005; 111(8): 1071 - 1077. [Abstract] [Full Text] [PDF]
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T. Senokuchi, T. Matsumura, M. Sakai, M. Yano, T. Taguchi, T. Matsuo, K. Sonoda, D. Kukidome, K. Imoto, T. Nishikawa, et al. Statins Suppress Oxidized Low Density Lipoprotein-induced Macrophage Proliferation by Inactivation of the Small G Protein-p38 MAPK Pathway J. Biol. Chem., February 25, 2005; 280(8): 6627 - 6633. [Abstract] [Full Text] [PDF]
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A. Undas, K. E. Brummel-Ziedins, and K. G. Mann Statins and Blood Coagulation Arterioscler. Thromb. Vasc. Biol., February 1, 2005; 25(2): 287 - 294. [Abstract] [Full Text] [PDF]
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Y. Birnbaum, Y. Ye, S. Rosanio, S. Tavackoli, Z.-Y. Hu, E. R. Schwarz, and B. F. Uretsky Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia-reperfusion injury Cardiovasc Res, February 1, 2005; 65(2): 345 - 355. [Abstract] [Full Text] [PDF]
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 A. Cordle and G. Landreth 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate {beta}-Amyloid-Induced Microglial Inflammatory Responses J. Neurosci., January 12, 2005; 25(2): 299 - 307. [Abstract] [Full Text] [PDF]
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 A. C. Newby Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic Plaque Rupture Physiol Rev, January 1, 2005; 85(1): 1 - 31. [Abstract] [Full Text] [PDF]
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L. Verschuren, R. Kleemann, E. H. Offerman, A. J. Szalai, S. J. Emeis, H. M. G. Princen, and T. Kooistra Effect of Low Dose Atorvastatin Versus Diet-Induced Cholesterol Lowering on Atherosclerotic Lesion Progression and Inflammation in Apolipoprotein E*3-Leiden Transgenic Mice Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 161 - 167. [Abstract] [Full Text] [PDF]
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 S Van Doornum, G McColl, and I P Wicks Atorvastatin reduces arterial stiffness in patients with rheumatoid arthritis Ann Rheum Dis, December 1, 2004; 63(12): 1571 - 1575. [Abstract] [Full Text] [PDF]
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