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.
KEYWORDS
Endothelial function - atherosclerosis - coronary artery disease - HMG-CoA reductase inhibitors - statins
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