Semin Vasc Med 2004; 4(4): 333-346
DOI: 10.1055/s-2004-869590
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Statins and Endothelial Dysfunction

Eric Larose1 , 2 , Peter Ganz1 , 2
  • 1Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
  • 2Cardiovascular Division, Harvard Medical School, Boston, Massachusetts
Further Information

Publication History

Publication Date:
29 April 2005 (online)

ABSTRACT

The endothelium integrates and modulates critical functions of the arterial wall. As well as regulating vasomotion, it controls inflammation, coagulation, and thrombosis. Many of these actions are mediated through the release of nitric oxide. Endothelial dysfunction is associated with atherosclerosis and its risk factors. It is independently correlated to adverse cardiovascular events, including myocardial infarction, coronary death, and the need for revascularization. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) protect against cardiovascular death, myocardial ischemia, myocardial infarction, and stroke. Although cholesterol reduction accounts for some of these benefits, others appear to be independent of cholesterol lowering. The endothelium mediates many of these “lipid-dependent” and “lipid-independent” actions of statins. This chapter reviews the effects of statins on endothelial dysfunction. To do so, a brief outline of the biology of the endothelium is a prerequisite. This will be followed by a summary of the advances in vascular research on cholesterol-dependent and cholesterol-independent effects of statins, with a focus on the endothelium. Ultimately, clinical relevance of observations derived from basic biology will be discussed.

REFERENCES

  • 1 Behrendt D, Ganz P. Endothelial function. From vascular biology to clinical applications.  Am J Cardiol. 2002;  90 40L-48L
  • 2 Furchgott R F, Zawadzki J V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.  Nature. 1980;  288 373-376
  • 3 Furchgott R F. The 1996 Albert Lasker Medical Research Awards. The discovery of endothelium-derived relaxing factor and its importance in the identification of nitric oxide.  JAMA. 1996;  276 1186-1188
  • 4 Ignarro L J, Buga G M, Wood K S, Byrns R E, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.  Proc Natl Acad Sci USA. 1987;  84 9265-9269
  • 5 Stuehr D J. Mammalian nitric oxide synthases.  Biochim Biophys Acta. 1999;  1411 217-230
  • 6 Kinlay S, Libby P, Ganz P. Endothelial function and coronary artery disease.  Curr Opin Lipidol. 2001;  12 383-389
  • 7 De Caterina R, Libby P, Peng H B et al.. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines.  J Clin Invest. 1995;  96 60-68
  • 8 Sarkar R, Meinberg E G, Stanley J C, Gordon D, Webb R C. Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells.  Circ Res. 1996;  78 225-230
  • 9 Cornwell T L, Arnold E, Boerth N J, Lincoln T M. Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP-dependent protein kinase by cGMP.  Am J Physiol. 1994;  267 C1405-C1413
  • 10 de Graaf J C, Banga J D, Moncada S, Palmer R M, de Groot P G, Sixma J J. Nitric oxide functions as an inhibitor of platelet adhesion under flow conditions.  Circulation. 1992;  85 2284-2290
  • 11 Diodati J G, Dakak N, Gilligan D M, Quyyumi A A. Effect of atherosclerosis on endothelium-dependent inhibition of platelet activation in humans.  Circulation. 1998;  98 17-24
  • 12 Hogg N, Kalyanaraman B, Joseph J, Struck A, Parthasarathy S. Inhibition of low-density lipoprotein oxidation by nitric oxide. Potential role in atherogenesis.  FEBS Lett. 1993;  334 170-174
  • 13 Yang Y, Loscalzo J. Regulation of tissue factor expression in human microvascular endothelial cells by nitric oxide.  Circulation. 2000;  101 2144-2148
  • 14 Bouchie J L, Hansen H, Feener E P. Natriuretic factors and nitric oxide suppress plasminogen activator inhibitor-1 expression in vascular smooth muscle cells. Role of cGMP in the regulation of the plasminogen system.  Arterioscler Thromb Vasc Biol. 1998;  18 1771-1779
  • 15 Busse R, Edwards G, Feletou M, Fleming I, Vanhoutte P M, Weston A H. EDHF: bringing the concepts together.  Trends Pharmacol Sci. 2002;  23 374-380
  • 16 Ganz P, Vita J A. Testing endothelial vasomotor function: nitric oxide, a multipotent molecule.  Circulation. 2003;  108 2049-2053
  • 17 Palmer R M, Ashton D S, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine.  Nature. 1988;  333 664-666
  • 18 Uematsu M, Ohara Y, Navas J P et al.. Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress.  Am J Physiol. 1995;  269 C1371-C1378
  • 19 Woodman C R, Muller J M, Rush J W, Laughlin M H, Price E M. Flow regulation of ecNOS and Cu/Zn SOD mRNA expression in porcine coronary arterioles.  Am J Physiol. 1999;  276 H1058-H1063
  • 20 Awolesi M A, Sessa W C, Sumpio B E. Cyclic strain upregulates nitric oxide synthase in cultured bovine aortic endothelial cells.  J Clin Invest. 1995;  96 1449-1454
  • 21 Harris M B, Blackstone M A, Ju H, Venema V J, Venema R C. Heat-induced increases in endothelial NO synthase expression and activity and endothelial NO release.  Am J Physiol Heart Circ Physiol. 2003;  285 H333-H340
  • 22 Hirata K, Miki N, Kuroda Y, Sakoda T, Kawashima S, Yokoyama M. Low concentration of oxidized low-density lipoprotein and lysophosphatidylcholine upregulate constitutive nitric oxide synthase mRNA expression in bovine aortic endothelial cells.  Circ Res. 1995;  76 958-962
  • 23 Zembowicz A, Tang J L, Wu K K. Transcriptional induction of endothelial nitric oxide synthase type III by lysophosphatidylcholine.  J Biol Chem. 1995;  270 17006-17010
  • 24 Inoue N, Venema R C, Sayegh H S, Ohara Y, Murphy T J, Harrison D G. Molecular regulation of the bovine endothelial cell nitric oxide synthase by transforming growth factor-beta 1.  Arterioscler Thromb Vasc Biol. 1995;  15 1255-1261
  • 25 Yoshizumi M, Perrella M A, Burnett Jr J C, Lee M E. Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life.  Circ Res. 1993;  73 205-209
  • 26 Forstermann U, Boissel J P, Kleinert H. Expressional control of the ‘constitutive’ isoforms of nitric oxide synthase (NOS I and NOS III).  FASEB J. 1998;  12 773-790
  • 27 Cosentino F, Hishikawa K, Katusic Z S, Luscher T F. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells.  Circulation. 1997;  96 25-28
  • 28 Olson S C, Dowds T A, Pino P A, Barry M T, Burke-Wolin T. ANG II stimulates endothelial nitric oxide synthase expression in bovine pulmonary artery endothelium.  Am J Physiol. 1997;  273 L315-L321
  • 29 Caulin-Glaser T, Garcia-Cardena G, Sarrel P, Sessa W C, Bender J R. 17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization.  Circ Res. 1997;  81 885-892
  • 30 Drummond G R, Cai H, Davis M E, Ramasamy S, Harrison D G. Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide.  Circ Res. 2000;  86 347-354
  • 31 Searles C D, Miwa Y, Harrison D G, Ramasamy S. Posttranscriptional regulation of endothelial nitric oxide synthase during cell growth.  Circ Res. 1999;  85 588-595
  • 32 Sessa W C, Pritchard K, Seyedi N, Wang J, Hintze T H. Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression.  Circ Res. 1994;  74 349-353
  • 33 Kanazawa K, Kawashima S, Mikami S et al.. Endothelial constitutive nitric oxide synthase protein and mRNA increased in rabbit atherosclerotic aorta despite impaired endothelium-dependent vascular relaxation.  Am J Pathol. 1996;  148 1949-1956
  • 34 Colin I M, Kopp P, Zbaren J, Haberli A, Grizzle W E, Jameson J L. Expression of nitric oxide synthase III in human thyroid follicular cells: evidence for increased expression in hyperthyroidism.  Eur J Endocrinol. 1997;  136 649-655
  • 35 Crabos M, Coste P, Paccalin M et al.. Reduced basal NO-mediated dilation and decreased endothelial NO-synthase expression in coronary vessels of spontaneously hypertensive rats.  J Mol Cell Cardiol. 1997;  29 55-65
  • 36 Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension.  N Engl J Med. 1995;  333 214-221
  • 37 Liu J, Garcia-Cardena G, Sessa W C. Palmitoylation of endothelial nitric oxide synthase is necessary for optimal stimulated release of nitric oxide: implications for caveolae localization.  Biochemistry. 1996;  35 13277-13281
  • 38 Feron O, Saldana F, Michel J B, Michel T. The endothelial nitric-oxide synthase-caveolin regulatory cycle.  J Biol Chem. 1998;  273 3125-3128
  • 39 Blair A, Shaul P W, Yuhanna I S, Conrad P A, Smart E J. Oxidized low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation.  J Biol Chem. 1999;  274 32512-32519
  • 40 Feron O, Belhassen L, Kobzik L, Smith T W, Kelly R A, Michel T. Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells.  J Biol Chem. 1996;  271 22810-22814
  • 41 Abu-Soud H M, Stuehr D J. Nitric oxide synthases reveal a role for calmodulin in controlling electron transfer.  Proc Natl Acad Sci U S A. 1993;  90 10769-10772
  • 42 Pou S, Pou W S, Bredt D S, Snyder S H, Rosen G M. Generation of superoxide by purified brain nitric oxide synthase.  J Biol Chem. 1992;  267 24173-24176
  • 43 Ju H, Zou R, Venema V J, Venema R C. Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity.  J Biol Chem. 1997;  272 18522-18525
  • 44 Busse R, Mulsch A. Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin.  FEBS Lett. 1990;  265 133-136
  • 45 Michel J B, Feron O, Sacks D, Michel T. Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin.  J Biol Chem. 1997;  272 15583-15586
  • 46 Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher A M. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation.  Nature. 1999;  399 601-605
  • 47 Montagnani M, Chen H, Barr V A, Quon M J. Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179).  J Biol Chem. 2001;  276 30392-30398
  • 48 Boo Y C, Jo H. Flow-dependent regulation of endothelial nitric oxide synthase: role of protein kinases.  Am J Physiol Cell Physiol. 2003;  285 C499-C508
  • 49 Chen Z P, Mitchelhill K I, Michell B J et al.. AMP-activated protein kinase phosphorylation of endothelial NO synthase.  FEBS Lett. 1999;  443 285-289
  • 50 Boo Y C, Sorescu G, Boyd N et al.. Shear stress stimulates phosphorylation of endothelial nitric-oxide synthase at Ser1179 by Akt-independent mechanisms: role of protein kinase A.  J Biol Chem. 2002;  277 3388-3396
  • 51 Butt E, Bernhardt M, Smolenski A et al.. Endothelial nitric-oxide synthase (type III) is activated and becomes calcium independent upon phosphorylation by cyclic nucleotide-dependent protein kinases.  J Biol Chem. 2000;  275 5179-5187
  • 52 Greif D M, Kou R, Michel T. Site-specific dephosphorylation of endothelial nitric oxide synthase by protein phosphatase 2A: evidence for crosstalk between phosphorylation sites.  Biochemistry. 2002;  41 15845-15853
  • 53 Fleming I, Fisslthaler B, Dimmeler S, Kemp B E, Busse R. Phosphorylation of Thr(495) regulates Ca(2+)/calmodulin-dependent endothelial nitric oxide synthase activity.  Circ Res. 2001;  88 E68-E75
  • 54 Gonzalez E, Kou R, Lin A J, Golan D E, Michel T. Subcellular targeting and agonist-induced site-specific phosphorylation of endothelial nitric-oxide synthase.  J Biol Chem. 2002;  277 39554-39560
  • 55 Garcia-Cardena G, Fan R, Shah V et al.. Dynamic activation of endothelial nitric oxide synthase by Hsp90.  Nature. 1998;  392 821-824
  • 56 Brouet A, Sonveaux P, Dessy C, Balligand J L, Feron O. Hsp90 ensures the transition from the early Ca2+-dependent to the late phosphorylation-dependent activation of the endothelial nitric-oxide synthase in vascular endothelial growth factor-exposed endothelial cells.  J Biol Chem. 2001;  276 32663-32669
  • 57 Benjamin I J, McMillan D R. Stress (heat shock) proteins: molecular chaperones in cardiovascular biology and disease.  Circ Res. 1998;  83 117-132
  • 58 Gratton J P, Fontana J, O'Connor D S, Garcia-Cardena G, McCabe T J, Sessa W C. Reconstitution of an endothelial nitric-oxide synthase (eNOS), hsp90, and caveolin-1 complex in vitro. Evidence that hsp90 facilitates calmodulin stimulated displacement of eNOS from caveolin-1.  J Biol Chem. 2000;  275 22268-22272
  • 59 Pritchard Jr K A, Ackerman A W, Gross E R et al.. Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion from endothelial nitric-oxide synthase.  J Biol Chem. 2001;  276 17621-17624
  • 60 Shastry S, Joyner M J. Geldanamycin attenuates NO-mediated dilation in human skin.  Am J Physiol Heart Circ Physiol. 2002;  282 H232-H236
  • 61 Takahashi S, Mendelsohn M E. Synergistic activation of endothelial nitric-oxide synthase (eNOS) by HSP90 and Akt: calcium-independent eNOS activation involves formation of an HSP90-Akt-CaM-bound eNOS complex.  J Biol Chem. 2003;  278 30821-30827
  • 62 Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.  Lancet. 1992;  339 572-575
  • 63 Essig M, Nguyen G, Prie D, Escoubet B, Sraer J D, Friedlander G. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins.  Circ Res. 1998;  83 683-690
  • 64 Buga G M, Griscavage J M, Rogers N E, Ignarro L J. Negative feedback regulation of endothelial cell function by nitric oxide.  Circ Res. 1993;  73 808-812
  • 65 Goldstein S, Czapski G. The reaction of NO. with O2.- and HO2.: a pulse radiolysis study.  Free Radic Biol Med. 1995;  19 505-510
  • 66 Guzik T J, West N E, Black E et al.. Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors.  Circ Res. 2000;  86 E85-E90
  • 67 Shishehbor M H, Aviles R J, Brennan M L et al.. Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy.  JAMA. 2003;  289 1675-1680
  • 68 Vasquez-Vivar J, Kalyanaraman B, Martasek P et al.. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors.  Proc Natl Acad Sci U S A. 1998;  95 9220-9225
  • 69 Laursen J B, Somers M, Kurz S et al.. Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin.  Circulation. 2001;  103 1282-1288
  • 70 Darley-Usmar V M, Hogg N, O'Leary V J, Wilson M T, Moncada S. The simultaneous generation of superoxide and nitric oxide can initiate lipid peroxidation in human low density lipoprotein.  Free Radic Res Commun. 1992;  17 9-20
  • 71 Libby P, Ridker P M, Maseri A. Inflammation and atherosclerosis.  Circulation. 2002;  105 1135-1143
  • 72 Bhagat K, Vallance P. Inflammatory cytokines impair endothelium-dependent dilatation in human veins in vivo.  Circulation. 1997;  96 3042-3047
  • 73 Gimbrone Jr M A. Vascular endothelium: an integrator of pathophysiologic stimuli in atherosclerosis.  Am J Cardiol. 1995;  75 67B-70B
  • 74 Ludmer P L, Selwyn A P, Shook T L et al.. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries.  N Engl J Med. 1986;  315 1046-1051
  • 75 Vita J A, Treasure C B, Nabel E G et al.. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease.  Circulation. 1990;  81 491-497
  • 76 Li J, Zhao S P, Li X P, Zhuo Q C, Gao M, Lu S K. Non-invasive detection of endothelial dysfunction in patients with essential hypertension.  Int J Cardiol. 1997;  61 165-169
  • 77 Williams S B, Cusco J A, Roddy M A, Johnstone M T, Creager M A. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus.  J Am Coll Cardiol. 1996;  27 567-574
  • 78 Di Carli M F, Janisse J, Grunberger G, Ager J. Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in diabetes.  J Am Coll Cardiol. 2003;  41 1387-1393
  • 79 Celermajer D S, Sorensen K E, Georgakopoulos D et al.. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults.  Circulation. 1993;  88 2149-2155
  • 80 Herrington D M, Braden G A, Williams J K, Morgan T M. Endothelial-dependent coronary vasomotor responsiveness in postmenopausal women with and without estrogen replacement therapy.  Am J Cardiol. 1994;  73 951-952
  • 81 Stamler J S, Loscalzo J. Endothelium-derived relaxing factor modulates the atherothrombogenic effects of homocysteine.  J Cardiovasc Pharmacol. 1992;  20(Suppl 12) S202-S204
  • 82 Tsurumi Y, Nagashima H, Ichikawa K, Sumiyoshi T, Hosoda S. Influence of plasma lipoprotein (a) levels on coronary vasomotor response to acetylcholine.  J Am Coll Cardiol. 1995;  26 1242-1250
  • 83 Chambers J C, McGregor A, Jean-Marie J, Obeid O A, Kooner J S. Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with vitamin C therapy.  Circulation. 1999;  99 1156-1160
  • 84 Williams S B, Goldfine A B, Timimi F K et al.. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo.  Circulation. 1998;  97 1695-1701
  • 85 Hink U, Li H, Mollnau H et al.. Mechanisms underlying endothelial dysfunction in diabetes mellitus.  Circ Res. 2001;  88 E14-E22
  • 86 Cayatte A J, Palacino J J, Horten K, Cohen R A. Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits.  Arterioscler Thromb. 1994;  14 753-759
  • 87 Leeson C P, Hingorani A D, Mullen M J et al.. Glu298Asp endothelial nitric oxide synthase gene polymorphism interacts with environmental and dietary factors to influence endothelial function.  Circ Res. 2002;  90 1153-1158
  • 88 Davis S F, Yeung A C, Meredith I T et al.. Early endothelial dysfunction predicts the development of transplant coronary artery disease at 1 year posttransplant.  Circulation. 1996;  93 457-462
  • 89 Fichtlscherer S, Rosenberger G, Walter D H, Breuer S, Dimmeler S, Zeiher A M. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease.  Circulation. 2000;  102 1000-1006
  • 90 Pasceri V, Willerson J T, Yeh E T. Direct proinflammatory effect of C-reactive protein on human endothelial cells.  Circulation. 2000;  102 2165-2168
  • 91 Treasure C B, Klein J L, Vita J A et al.. Hypertension and left ventricular hypertrophy are associated with impaired endothelium-mediated relaxation in human coronary resistance vessels.  Circulation. 1993;  87 86-93
  • 92 Corretti M C, Anderson T J, Benjamin E J et al.. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.  J Am Coll Cardiol. 2002;  39 257-265
  • 93 Ting H H, Timimi F K, Haley E A, Roddy M A, Ganz P, Creager M A. Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia.  Circulation. 1997;  95 2617-2622
  • 94 Anderson T J, Uehata A, Gerhard M D et al.. Close relation of endothelial function in the human coronary and peripheral circulations.  J Am Coll Cardiol. 1995;  26 1235-1241
  • 95 Oliver J J, Webb D J. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events.  Arterioscler Thromb Vasc Biol. 2003;  23 554-566
  • 96 Kuvin J T, Patel A R, Sliney K A et al.. Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude.  Am Heart J. 2003;  146 168-174
  • 97 Bonetti P O, Barsness G W, Keelan P C et al.. Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease.  J Am Coll Cardiol. 2003;  41 1761-1768
  • 98 Coresh J, Kwiterovich Jr P O. Small, dense low-density lipoprotein particles and coronary heart disease risk: A clear association with uncertain implications.  JAMA. 1996;  276 914-915
  • 99 Sacks F M, Katan M. Randomized clinical trials on the effects of dietary fat and carbohydrate on plasma lipoproteins and cardiovascular disease.  Am J Med. 2002;  113(Suppl 9B) 13S-24S
  • 100 Grundy S M, Balady G J, Criqui M H et al.. When to start cholesterol-lowering therapy in patients with coronary heart disease. A statement for healthcare professionals from the American Heart Association Task Force on Risk Reduction.  Circulation. 1997;  95 1683-1685
  • 101 Gordon B R, Kelsey S F, Dau P C et al.. Long-term effects of low-density lipoprotein apheresis using an automated dextran sulfate cellulose adsorption system. Liposorber Study Group.  Am J Cardiol. 1998;  81 407-411
  • 102 Buchwald H, Varco R L, Boen J R et al.. Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: five-year posttrial follow-up report from the POSCH. Program on the Surgical Control of the Hyperlipidemias.  Arch Intern Med. 1998;  158 1253-1261
  • 103 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) . Lancet. 1994;  344 1383-1389
  • 104 Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels . The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.  N Engl J Med. 1998;  339 1349-1357
  • 105 Sacks F M, Pfeffer M A, Moye L A et al.. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.  N Engl J Med. 1996;  335 1001-1009
  • 106 Heart Protection Study Collaborative Group . MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.  Lancet. 2002;  360 7-22
  • 107 Shepherd J, Cobbe S M, 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
  • 108 Downs J R, Clearfield M, Weis S et al.. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.  JAMA. 1998;  279 1615-1622
  • 109 Sever P S, Dahlof B, Poulter N R et al.. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.  Lancet. 2003;  361 1149-1158
  • 110 Istvan E S, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase.  Science. 2001;  292 1160-1164
  • 111 Maron D J, Fazio S, Linton M F. Current perspectives on statins.  Circulation. 2000;  101 207-213
  • 112 Jones P H, Davidson M H, Stein E A et al.. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial).  Am J Cardiol. 2003;  92 152-160
  • 113 Cannon C P, Braunwald E, McCabe C H et al.. Intensive versus moderate lipid lowering with statins after acute coronary syndromes.  N Engl J Med. 2004;  350 1495-1504
  • 114 Ridker P M, Rifai N, Lowenthal S P. Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia.  Circulation. 2001;  103 1191-1193
  • 115 Kinlay S, Schwartz G G, Olsson A G et al.. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study.  Circulation. 2003;  108 1560-1566
  • 116 Schwartz G G, Olsson A G, Ezekowitz M D et al.. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.  JAMA. 2001;  285 1711-1718
  • 117 Buchwald H, Williams S E, Matts J P, Nguyen P A, Boen J R. Overall mortality in the program on the surgical control of the hyperlipidemias.  J Am Coll Surg. 2002;  195 327-331
  • 118 Williams J K, Sukhova G K, Herrington D M, Libby P. Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys.  J Am Coll Cardiol. 1998;  31 684-691
  • 119 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
  • 120 Jones S P, Gibson M F, Rimmer III D M, Gibson T M, Sharp B R, Lefer D J. Direct vascular and cardioprotective effects of rosuvastatin, a new HMG-CoA reductase inhibitor.  J Am Coll Cardiol. 2002;  40 1172-1178
  • 121 John S, Delles C, Jacobi J et al.. Rapid improvement of nitric oxide bioavailability after lipid-lowering therapy with cerivastatin within two weeks.  J Am Coll Cardiol. 2001;  37 1351-1358
  • 122 O'Driscoll G, Green D, Taylor R R. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month.  Circulation. 1997;  95 1126-1131
  • 123 Dupuis J, Tardif J C, Cernacek P, Theroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (reduction of cholesterol in ischemia and function of the endothelium) trial.  Circulation. 1999;  99 3227-3233
  • 124 Laufs U, Wassmann S, Hilgers S, Ribaudo N, Bohm M, Nickenig G. Rapid effects on vascular function after initiation and withdrawal of atorvastatin in healthy, normocholesterolemic men.  Am J Cardiol. 2001;  88 1306-1307
  • 125 Tamai O, Matsuoka H, Itabe H, Wada Y, Kohno K, Imaizumi T. Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans.  Circulation. 1997;  95 76-82
  • 126 Cai H, Harrison D G. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress.  Circ Res. 2000;  87 840-844
  • 127 Rikitake Y, Kawashima S, Takeshita S et al.. Anti-oxidative properties of fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of atherosclerosis in cholesterol-fed rabbits.  Atherosclerosis. 2001;  154 87-96
  • 128 Laufs U, La Fata V, Plutzky J, Liao J K. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors.  Circulation. 1998;  97 1129-1135
  • 129 Liao J K, Shin W S, Lee W Y, Clark S L. Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase.  J Biol Chem. 1995;  270 319-324
  • 130 Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J et al.. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells.  J Clin Invest. 1998;  101 2711-2719
  • 131 Li D, Mehta J L. Upregulation of endothelial receptor for oxidized LDL (LOX-1) by oxidized LDL and implications in apoptosis of human coronary artery endothelial cells: evidence from use of antisense LOX-1 mRNA and chemical inhibitors.  Arterioscler Thromb Vasc Biol. 2000;  20 1116-1122
  • 132 Mehta J L, Li D Y, Chen H J, Joseph J, Romeo F. Inhibition of LOX-1 by statins may relate to upregulation of eNOS.  Biochem Biophys Res Commun. 2001;  289 857-861
  • 133 Feron O, Dessy C, Moniotte S, Desager J P, Balligand J L. Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase.  J Clin Invest. 1999;  103 897-905
  • 134 Feron O, Dessy C, Desager J P, Balligand J L. Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance.  Circulation. 2001;  103 113-118
  • 135 Laufs U, Fata V L, Liao J K. Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase.  J Biol Chem. 1997;  272 31725-31729
  • 136 Wassmann S, Laufs U, Muller K et al.. Cellular antioxidant effects of atorvastatin in vitro and in vivo.  Arterioscler Thromb Vasc Biol. 2002;  22 300-305
  • 137 Kaesemeyer W H, Caldwell R B, Huang J, Caldwell R W. Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions.  J Am Coll Cardiol. 1999;  33 234-241
  • 138 Goldstein J L, Brown M S. Regulation of the mevalonate pathway.  Nature. 1990;  343 425-430
  • 139 Amano M, Ito M, Kimura K et al.. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase).  J Biol Chem. 1996;  271 20246-20249
  • 140 Kimura K, Ito M, Amano M et al.. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase).  Science. 1996;  273 245-248
  • 141 Feng J, Ito M, Kureishi Y et al.. Rho-associated kinase of chicken gizzard smooth muscle.  J Biol Chem. 1999;  274 3744-3752
  • 142 Riento K, Ridley A J. Rocks: multifunctional kinases in cell behaviour.  Nat Rev Mol Cell Biol. 2003;  4 446-456
  • 143 Laufs U, Liao J K. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase.  J Biol Chem. 1998;  273 24266-24271
  • 144 Laufs U, Endres M, Stagliano N et al.. Neuroprotection mediated by changes in the endothelial actin cytoskeleton.  J Clin Invest. 2000;  106 15-24
  • 145 Brouet A, Sonveaux P, Dessy C, Moniotte S, Balligand J L, Feron O. Hsp90 and caveolin are key targets for the proangiogenic nitric oxide-mediated effects of statins.  Circ Res. 2001;  89 866-873
  • 146 Kureishi Y, Luo Z, Shiojima I et al.. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals.  Nat Med. 2000;  6 1004-1010
  • 147 Laufs U, Endres M, Custodis F et al.. Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of Rho GTPase gene transcription.  Circulation. 2000;  102 3104-3110
  • 148 Uehata M, Ishizaki T, Satoh H et al.. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension.  Nature. 1997;  389 990-994
  • 149 Mukai Y, Shimokawa H, Matoba T et al.. Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension.  FASEB J. 2001;  15 1062-1064
  • 150 Masumoto A, Hirooka Y, Shimokawa H, Hironaga K, Setoguchi S, Takeshita A. Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans.  Hypertension. 2001;  38 1307-1310
  • 151 Utsunomiya T, Satoh S, Ikegaki I, Toshima Y, Asano T, Shimokawa H. Antianginal effects of hydroxyfasudil, a Rho-kinase inhibitor, in a canine model of effort angina.  Br J Pharmacol. 2001;  134 1724-1730
  • 152 Masumoto A, Mohri M, Shimokawa H, Urakami L, Usui M, Takeshita A. Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina.  Circulation. 2002;  105 1545-1547
  • 153 Laufs U, Gertz K, Dirnagl U, Bohm M, Nickenig G, Endres M. Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice.  Brain Res. 2002;  942 23-30
  • 154 Gertz K, Laufs U, Lindauer U et al.. Withdrawal of statin treatment abrogates stroke protection in mice.  Stroke. 2003;  34 551-557
  • 155 Andrews T C, Raby K, Barry J et al.. Effect of cholesterol reduction on myocardial ischemia in patients with coronary disease.  Circulation. 1997;  95 324-328
  • 156 Libby P. Inflammation in atherosclerosis.  Nature. 2002;  420 868-874
  • 157 Tomita H, Egashira K, Kubo-Inoue M et al.. Inhibition of NO synthesis induces inflammatory changes and monocyte chemoattractant protein-1 expression in rat hearts and vessels.  Arterioscler Thromb Vasc Biol. 1998;  18 1456-1464
  • 158 Ni W, Egashira K, Kataoka C et al.. Antiinflammatory and antiarteriosclerotic actions of HMG-CoA reductase inhibitors in a rat model of chronic inhibition of nitric oxide synthesis.  Circ Res. 2001;  89 415-421
  • 159 Miyata K, Shimokawa H, Kandabashi T et al.. Rho-kinase is involved in macrophage-mediated formation of coronary vascular lesions in pigs in vivo.  Arterioscler Thromb Vasc Biol. 2000;  20 2351-2358
  • 160 Shimizu K, Aikawa M, Takayama K, Libby P, Mitchell R N. Direct anti-inflammatory mechanisms contribute to attenuation of experimental allograft arteriosclerosis by statins.  Circulation. 2003;  108 2113-2120
  • 161 Stalker T J, Lefer A M, Scalia R. A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium: the role of mevalonic acid.  Br J Pharmacol. 2001;  133 406-412
  • 162 Laufs U, Marra D, Node K, Liao J K. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing Rho GTPase-induced down-regulation of p27(Kip1).  J Biol Chem. 1999;  274 21926-21931
  • 163 Shimokawa H, Morishige K, Miyata K et al.. Long-term inhibition of Rho-kinase induces a regression of arteriosclerotic coronary lesions in a porcine model in vivo.  Cardiovasc Res. 2001;  51 169-177
  • 164 Fukumoto Y, Libby P, Rabkin E et al.. Statins alter smooth muscle cell accumulation and collagen content in established atheroma of Watanabe heritable hyperlipidemic rabbits.  Circulation. 2001;  103 993-999
  • 165 Wassmann S, Laufs U, Baumer A T et al.. HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species.  Hypertension. 2001;  37 1450-1457
  • 166 Shishehbor M H, Brennan M L, Aviles R J et al.. Statins promote potent systemic antioxidant effects through specific inflammatory pathways.  Circulation. 2003;  108 426-431
  • 167 Hattori Y, Nakanishi N, Kasai K. Statin enhances cytokine-mediated induction of nitric oxide synthesis in vascular smooth muscle cells.  Cardiovasc Res. 2002;  54 649-658
  • 168 Bourcier T, Libby P. HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells.  Arterioscler Thromb Vasc Biol. 2000;  20 556-562
  • 169 Gaddam V, Li D Y, Mehta J L. Anti-thrombotic effects of atorvastatin-an effect unrelated to lipid lowering.  J Cardiovasc Pharmacol Ther. 2002;  7 247-253
  • 170 Weitz-Schmidt G, Welzenbach K, Brinkmann V et al.. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site.  Nat Med. 2001;  7 687-692
  • 171 Henwood J M, Heel R C. Lovastatin. A preliminary review of its pharmacodynamic properties and therapeutic use in hyperlipidaemia.  Drugs. 1988;  36 429-454
  • 172 Todd P A, Goa K L. Simvastatin. A review of its pharmacological properties and therapeutic potential in hypercholesterolaemia.  Drugs. 1990;  40 583-607
  • 173 Malhotra H S, Goa K L. Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia.  Drugs. 2001;  61 1835-1881
  • 174 Plosker G L, Wagstaff A J. Fluvastatin: a review of its pharmacology and use in the management of hypercholesterolaemia.  Drugs. 1996;  51 433-459
  • 175 Carswell C I, Plosker G L, Jarvis B. Rosuvastatin.  Drugs. 2002;  62 2075-2085
  • 176 Serajuddin A T, Ranadive S A, Mahoney E M. Relative lipophilicities, solubilities, and structure-pharmacological considerations of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors pravastatin, lovastatin, mevastatin, and simvastatin.  J Pharm Sci. 1991;  80 830-834
  • 177 Bolego C, Poli A, Cignarella A, Catapano A L, Paoletti R. Novel statins: pharmacological and clinical results.  Cardiovasc Drugs Ther. 2002;  16 251-257
  • 178 Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F. New insights into the pharmacodynamic and pharmacokinetic properties of statins.  Pharmacol Ther. 1999;  84 413-428
  • 179 van Wissen S, Trip M D, Smilde T J, de Graaf J, Stalenhoef A F, Kastelein J J. Differential hs-CRP reduction in patients with familial hypercholesterolemia treated with aggressive or conventional statin therapy.  Atherosclerosis. 2002;  165 361-366
  • 180 van de Ree M A, Huisman M V, Princen H M, Meinders A E, Kluft C. Strong decrease of high sensitivity C-reactive protein with high-dose atorvastatin in patients with type 2 diabetes mellitus.  Atherosclerosis. 2003;  166 129-135
  • 181 Taylor A J, Kent S M, Flaherty P J, Coyle L C, Markwood T T, Vernalis M N. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness.  Circulation. 2002;  106 2055-2060
  • 182 Nissen S, Tuzcu E, Schoenhagen P, Brown B G. Effect of Intensive Compared With Moderate Lipid-Lowering Therapy on Progression of Coronary Atherosclerosis.  JAMA. 2004;  291 1071-1080

Eric LaroseD.V.M. M.D. 

Cardiovascular Division, Brigham and Women's Hospital

75 Francis Street, Tower 3A, Boston, MA 02115

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