New nonlipid effects of statins and their clinical relevance in cardiovascular disease

Summary

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, statins, have been demonstrated to reduce cardiovascular morbidity and mortality in patients with a wide range of cholesterol levels. Numerous cholesterol-independent effects of statins that may limit atherosclerosis are probably related to inhibition of the geranylgeranylation of GTP-binding intracellular signaling proteins and involve: improved vasoreactivity, mostly through increased NO bioavailability; decreased expression of proinflammatory cytokines (interleukin-6, interleukin-1β, tumor necrosis factor α), C-reactive protein, chemokines, matrix metalloproteinases, and tissue factor with the subsequent inhibition of thrombin generation; reduced platelet activity; increased thrombomodulin expression; enhanced fibrinolysis, regulation of angiogenesis and immunomodulation. However, the clinical relevance of multiple protective effects induced by statins has not been clarified yet.

Keywords

Statins - lipids - atherosclerosis

• References

• 1 Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systemic review and meta-analysis. BMJ 2003; 326: 1423.
• 2 Blumenthal RS. Statins: effective antiatherosclerotic therapy. Am Heart J 2000; 139: 577-83.
• 3 Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins. Implications for cardiovascular event reduction. JAMA 1998; 279: 1643-50.
• 4 Koh KK. Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability. Cardiovasc Res 2000; 47: 648-57.
• 5 Undas A, Brozek J, Musial J. Anti-inflammatory and anti-thrombotic effects of statins in the management of coronary artery disease. Clin Lab 2002; 48: 287-96.
• 6 Krysiak R, Okopień B, Herman ZS. Effects of HMG-CoA reductase inhibitors on coagulation and fibrinolysis processes. Drugs 2003; 63: 1821-54.
• 7 Casey PJ. Protein lipidation in cell signaling. Science 1995; 268: 221-5.
• 8 Maltese WA. Posttranslational modification of proteins by isoprenoids in mammalian cells. FASEB J 1990; 04: 3319-28.
• 9 Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 2003; 23: 168-75.
• 10 Laufs U, La VFata, Plutzky J. et al. Upregulation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors. Circulation 1998; 97: 1129-35.
• 11 Kalinowski L, Dobrucki LW, Brovkovych V. et al. Increased nitric oxide bioavailability in endothelial cells contributes to the pleiotropic effect of cerivastatin. Circulation 2002; 105: 933-8.
• 12 Wassmann S, Laufs U, Mueller K. et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo . Arterioscler Thromb Vasc Biol 2002; 22: 300-5.
• 13 Delbosc S, Morena M, Djouad F. et al. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are able to reduce superoxide anion production by NADPH oxidase in THP-1 derived monocytes. J Cardiovasc Pharmacol 2002; 40: 611-7.
• 14 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; 06: 1004-10.
• 15 Brouet A, Sonveaux P, Dessy C. et al. Hsp90 and caveolin are key targets for the proangiogenic nitric oxide-mediated effects of statins. Circ Res 2001; 89: 866-73.
• 16 Feron O, Dessy C, Desager JP. et al. Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes eNOS activation through a decrease in caveolin abundance. Circulation 2001; 103: 113-8.
• 17 Pritchard Jr KA, Ackerman AW, Gross ER. et al. Heat shock protein 90 mediates the balance of Na and superoxide anion from endothelial nitric oxide synthase. J Biol Chem 2001; 276: 17621-4.
• 18 Paiva H, Laakso J, Lehtimaki T. et al. Effect of high-dose statin treatment on plasma concentrations of endogenous nitric oxide synthase inhibitors. J Cardiovasc Pharmacol 2003; 41: 219-22.
• 19 Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J. et al. Effects of the 3-hydroxy-3methylglutaryl-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: 2711-9.
• 20 Seeger H, Mueck AO, Lippert TH. Fluvastatin increases prostacyclin and decreases endothelin production by human umbilical vein endothelial cells. Int J Pharmacol Ther 2000; 38: 270-2.
• 21 Vita JA, Yeung AC, Winniford M. et al. Effect of cholesterol-lowering therapy on coronary endothelial vasomotor function in patients with coronary artery disease. Circulation 2000; 102: 846-51.
• 22 Wilson SH, Simari RD, Best PJ. et al. Simvastatin preserves coronary endothelial function in hypercholesterolemia in the absence of lipid lowering. Arterioscler Thromb Vasc Biol 2001; 21: 122-8.
• 23 Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arterioscler Thromb Vasc Biol 2001; 21: 1712-9.
• 24 Lefer DJ. Statins as potent anti-inflammatory drugs. Circulation 2002; 106: 2041-2.
• 25 Laufs U, Wassemann S, Hikgers S. et al. Rapid effects on vascular function after initiation and withdrawal of atorvastatin in healthy, normocholesterolemic men. Am J Cardiol 2001; 88: 1306-7.
• 26 Tsunekawa T, Hayashi T, Kano H. et al. Cerivastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days. Circulation 2001; 104: 376-9.
• 27 Laufs U. Beyond lipid-lowering: effects of statins on endothelial nitric oxide. Eur J Clin Paharmacol 2003; 58: 719-31.
• 28 Corsini A, Mazzotti M, Raiteri M. et al. Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase. Atherosclerosis 1993; 101: 117-1 25.
• 29 Soma MR, Donetti E, Parolini C. et al. HMG CoA reductase inhibitors: in vivo effects on carotid intimal thickening in normocholesterolemic rabbits. Arterioscler Thromb 1993; 13: 571-8.
• 30 Corsini A, Pazzucconi F, Pfister P. et al. Inhibitor of proliferation of arterial smoothmuscle cells by fluvastatin. Lancet 1996; 348: 1584.
• 31 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 2002; 103: 993-9.
• 32 Hidaka Y, Eda T, Yanemoto M. et al. Inhibition of cultured vascular smooth muscle cell migration by simvastatin (MK-733). Atherosclerosis 1992; 95: 87-94.
• 33 Axel DI, Riessen R, Runge H. et al. Effects of cerivastatin on human arterial smooth muscle cell proliferation and migration in transfilter cocultures. J Cardiovasc Pharmacol 2000; 35: 619-29.
• 34 Guijarro C, Blanco-Colio LM, Ortego M. et al. 3-Hydroxy-3-methylglutaryl coenzyme A reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circ Res 1998; 83: 490-500.
• 35 Erl W, Hristov M, Neureuter M. et al. HMGCoA reductase inhibitors induce apoptosis in neointima-derived vascular smooth muscle cells. Atherosclerosis 2003; 169: 251-8.
• 36 Kaneta S, Satoh K, Kano S. et al. All hydrophobic HMG-CoA reductase inhibitors induce apoptotic death in rat pulmonary vein endothelial cells. Atherosclerosis 2003; 170: 237-43.
• 37 Danesh J, Whincup P, Walker M. et al. Low grade inflammation and coronary artery disease: prospective study and updated metaanalyses. BMJ 2000; 321: 199-204.
• 38 Ridker PM, Rifai N, Pfeffer MA. et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1998; 98: 839-44.
• 39 Ridker PM, Rifai N, Clearfield M. et al. Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344: 1959-65.
• 40 Albert MA, Danielson E, Rifai N. et al. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001; 286: 64-70.
• 41 Jialal I, Stein D, Balis D. et al. Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive Creactive protein levels. Circulation 2001; 103: 1933-5.
• 42 Plenge JK, Hernandez TL, Weil KM. et al. Simvastatin lowers C-reactive protein within 14 days. An effect independent of low-density lipoprotein cholesterol reduction. Circulation 2002; 106: 1447-52.
• 43 Ridker PM, Rifai N, Pitman M. et al. Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation 2001; 103: 1191-3.
• 44 Ridker PM, Rifai N, Stampfer MJ. et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767-72.
• 45 Volpato S, Guralnik JM, Ferrucci L. et al. Cardiovascular disease, interleukin-6, and risk of mortality in older women: the Women’s health and Aging Study. Circulation 2001; 103: 947-53.
• 46 Rosenson RS, Tangney CC, Casey LC. Inhibition of proinflammatory cytokine prduction by pravastatin. Lancet 1999; 353: 983-4.
• 47 Musial J, Undas A, Gajewski P. et al. Antiinflammatory effects of simvastatin in subjects with hypercholesterolemia. Int J Cardiol 2001; 77: 247-53.
• 48 Ferro D, Parrotto S, Basili S. et al. Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia. J Am Coll Cardiol 2000; 36: 427-31.
• 49 Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999; 340: 448-51.
• 50 Ferro D, Parrotto S, Basili S. et al. Lipophilic HMG-CoA reductase inhibitor has an antiinflammatory effect: reduction of mRNA levels for interleukin-1β, interleukin-6, cyclooxygenase-2, and p22phox by regulating of peroxisome proliferator-activated receptor-α (PPAR-α) in primary endothelial cells. Life Sci 2000; 67: 863-76.
• 51 Meroni PL, Tremoli E. Modulation of adhesion molecule expression on endothelial cells: to be or not to be?. J Thromb Haemost 2003; 01: 2280-2.
• 52 Meroni PL, Raschi E, Testoni C. et al. Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype. Arthritis Rheum 2001; 44: 2870-8.
• 53 Rezaie-Majd A, Prager GW, Bucek RA. et al. Simvastatin reduces the expression of adhesion molecules in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 2003; 23: 397-403.
• 54 Dimitrova Y, Dunoyer-Geindre S, Reber G. et al. Effects of statins on adhesion molecule expression in endothelial cells. J Thromb Haemost 2003; 01: 2290-9.
• 55 Schmidt A, Goepfert C, Feitsma K. et al. Lovastatin-stimulated superinduction of Eselectin, ICAM-1and VCAM-1 to TNF-alpha activated human vascular endothelial cells. Atherosclerosis 2002; 164: 57-64.
• 56 Rosenson RS, Wolff D, Tangney CC. Statins reduce oxidized low-density lipoprotein levels, but do not alter soluble intercellular celladhesion molecule-1 and vascular cell-adhesion molecule-1 levels in subjects with hypercholesterolemia. Clin Sci (Lond) 2004; 106: 215-7.
• 57 Nubel T, Dippold W, Kleinert H. et al. Lovastatin inhibits Rho-regulated expression of E-selectin by TNFalpha and attenuates tumor cell adhesion. FASEB J 2004; 18: 140-2.
• 58 Weitz-Schmidt G, Welzenbach K, Brinkmann V. et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nature Med 2001; 07: 687-92.
• 59 Grip O, Janciauskiene S, Lindgren S. Pravastatin down-regulates inflammatory mediators in human monocytes in vitro . Eur J Pharmacol 2000; 410: 83-92.
• 60 Kirsch C, Eckert GP, Mueller WE. Statin effects on cholesterol micro-domains in brain plasma membranes. Biochem Pharmacol 2003; 65: 843-56.
• 61 Tilghman RW, Hoover RL. E-selctin and ICAM-1 are incorporated into detergentinsoluble membrane domains following clustering in endothelial cells. FEBS Lett 2002; 525: 83-7.
• 62 Marwali MR, Rey-Ladino J, Dreolini L. et al. Membrane cholesterol regulates LFA-1 function and lipid raft heterogenoisity. Blood 2003; 102: 215-22.
• 63 Romano M, Diomede L, Sironi M. et al. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest 2000; 80: 1095-100.
• 64 Pasceri V, Chang J, Willerson JT. et al. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-athero-sclerosis drugs. Circulation 2001; 103: 2531-4.
• 65 Brandes RP, Beer S, Ha T. et al. Withdrawal of cerivastatin induces monocyte chemoattractant protein 1 and tissue factor expression in cultured vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2003; 23: 1794-800.
• 66 Crisby M, Nordin-Fredriksson G, Shah PK. et al. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation 2001; 103: 926-33.
• 67 Waehre T, Damas JK, Gullestad L. et al. Hydroxymethylglutaryl coenzyme A reductase inhibitors down-regulate chemokines and chemokine receptors in patients with coronary artery disease. J Am Coll Cardiol 2003; 41: 1460-7.
• 68 Luan Z, Chase AJ, Newby AC. Statins inhibit secretion of metalloproteinases-1, -2, -3, and –9 from vascular smooth muscle cells and macrophages. Arterioscler Thromb Vasc Biol 2003; 23: 769-75.
• 69 Aikawa M, Rabkin E, Sugiyama S. et al. An HMG-CoA reductase inhibitor, cervastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro . Circulation 2001; 103: 276-83.
• 70 Schonbeck U, Gerdes N, Varo N. et al. Oxidized low-density lipoprotein augments and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors limit CD40 and CD40L expression in human vascular cells. Circulation 2002; 106: 2888-93.
• 71 Mulhaupt F, Matter CM, Kwak BR. et al. Statins (HMG-CoA reductase inhibitor) reduce CD40 expression in human vascular cells. Cardiovasc Res 2003; 59: 755-66.
• 72 Cipollone F, Mezzetti A, Porreca E. et al. Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy. Circulation 2002; 106: 399-402.
• 73 Semb AG, van Wissen S, Ueland T. et al. Raised levels of soluble CD40L in patients with familial hypercholesterolemia: downregulatory effect of statin therapy. J Am Coll Cardiol 2003; 41: 275-9.
• 74 Libby P, Simon DI. Inflammation and thrombosis: the clot thickens. Circulation 2001; 103: 1718-20.
• 75 Anand SX, Viles-Gonzalez JF, Badimon JJ. et al. Membrane-associated CD40L and sCD40L in atherothrombotic disease. Thromb Haemost 2003; 90: 377-84.
• 76 Almong Y. Statins, inflammation, and sepsis: hypothesis. Chest 2003; 124: 740-3.
• 77 Wagner AH, Schwabe O, Hecker M. Atorvastatin inhibition of cytokine-inducible nitric oxide synthase expression in native endothelial cells in situ. Br J Pharmacol 2002; 136: 143-9.
• 78 Kothe H, Dalhoff K, Rupp J. et al. Hydroxymethylglutaryl coenzyme A reductase inhibitors modify the inflammatory response of human macrophages and endothelial cells infected with Chlamydia pneumoniae . Circulation 2000; 101: 1760-3.
• 79 Dechend R, Gieffers J, Dietz R. et al. Hydroxymethylglutaryl coenzyme A reductase inhibition reduces Chlamydia pneumoniae-induced cell interaction and activation. Circulation 2003; 108: 261-5.
• 80 Colli S, Eligini S, Lalli M. et al. Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol 1997; 17: 265-72.
• 81 Ferro D, Basili S, Alessandri C. et al. Inhibition of tissue-factor-mediated thrombin generation by simvastatin. Atherosclerosis 2000; 149: 111-6.
• 82 Bea F, Blessing E, Shelley MI. et al. Simvastatin inhibits expression of tissue factor in advanced atherosclerotic lesions of apolipoprotein E deficient mice independently of lipid lowering. Atherosclerosis 2003; 167: 187-94.
• 83 Baetta R, Camera M, Comparato C. et al. Fluvastatin reduces tissue factor expression and macrophage accumulation in carotid lesions of cholesterol-fed rabbits in absence of lipid lowering. Arterioscler Thromb Vasc Biol 2002; 22: 692-8.
• 84 Eto M, Kozai T, Cosentino F. et al. Statin prevents tissue factor expression in human endothelial cells. Role of Rho/Rho-kinase and Akt pathways. Circulation 2002; 105: 1756-9.
• 85 Cortellaro M, Cofrancesco E, Arbustini E. et al. Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study. Thromb Haemost 2002; 88: 41-47.
• 86 Szczeklik A, Musial J, Undas A. et al. Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia. J Am Coll Cardiol 1999; 33: 1286-93.
• 87 Musial J, Undas A, Undas R. et al. Treatment with simvastatin and low dose aspirin depresses thrombin generation in patients with coronary heart disease and borderline high cholesterol levels. Thromb Haemost 2001; 85: 221-5.
• 88 Undas A, Brummel KE, Musial J. et al. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation 2001; 103: 2248-53.
• 89 Joukhadar C, Klein N, Prinz M. et al. Similar efects of atorvastatin, simvastatin and pravastatin on thrombogenic and inflammatory parameters in patients with hypercholesterolemia. Thromb Haemost 2001; 85: 47-51.
• 90 Wada H, Mori Y, Kaneko T. et al. Elevated plasma levels of vascular endothelial cell markers in patients with hypercholesterolemia. Am J Haematol 1993; 44: 112-6.
• 91 Ambrosi P, Aillaud MF, Habib G. et al. Fluvastatin decreases soluble thrombomodulin in cardiac transplant recipients. Thromb Haemost 2000; 83: 46-48.
• 92 Masamura K, Oida K, Kanehara H. et al. Pitavastatin-induced thrombomodulin expression by endothelial cells acts via inhibition small G proteins of the Rho family. Arterioscler Thromb Vasc Biol 2003; 23: 512-7.
• 93 Shi J, Wang J, Zheng H. et al. Statins increase thrombomodulin expression and function in human endothelial cells by a nitric-oxidedependent mechanism and counteract tumor necrosis factor alpha-induced thrombomodulin downregulation. Blood Coagul Fibrinolysis 2003; 14: 575-85.
• 94 Huhle G, Abletshauser C, Mayer N. et al. Reduction of platelet activity markers in type II hypercholesterolemic patients by a HMGCoA-reductase inhibitor. Thromb Res 1999; 95: 229-34.
• 95 Puccetti L, Pasqui AL, Pastorelli M. et al. Time-dependent effect of statins on platelet function in hypercholesterolemia. Eur J Clin Invest 2002; 32: 901-8.
• 96 Dujovne CA, Harris WS, Altman R. et al. Effect of atorvastatin on hemorheologichemostatic parameters and serum fibrinogen levels in hyperlipidemic patients. Am J Cardiol 2000; 85: 350-3.
• 97 Notarbartolo A, Davi G, Averna M. et al. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia. Arterioscler Thromb Vasc Biol 1995; 15: 247-51.
• 98 Tannous M, Cheung R, Vignini A. et al. Atorvastatin increases eNOS levels in human platelets of hyperlipidemic subjects. Thromb Haemost 1999; 82: 1390-4.
• 99 Laufs U, Gertz K, Huang P. et al. Atorvastatin upregulates type III nitric oxide synthase in thrombocytes decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke 2000; 31: 2437-49.
• 100 Kaneider NC, Egger P, Dunzendorfer S. et al. Rho-GTP-ase-dependent platelet-neutrophil interaction affected by HMG-CoA reductase inhibition with altered adenosine nucleotide release and function. Arterioscler Thromb Vasc Biol 2002; 22: 1029-35.
• 101 Ferroni P, Martini F, Cardarello CM. et al. Enhanced interleukin-1β in hypercholesterolemia. Effects of simvastatin and low-dose aspirin. Circulation 2003; 18: 1673-5.
• 102 Ruggeri Z. Platelets in atherothrombosis. Nat Med 2002; 08: 1227-34.
• 103 Lacoste L, Lam JYT, Hung J. et al. Hyperlipidemia and coronary disease. Correction of the increased thrombogenic potential with cholesterol reduction. Circulation 1995; 92: 3172-7.
• 104 Aoki I, Aoki N, Kawano K. et al. Platelet dependent thrombin generation in patients with hyperlipidemia. J Am Coll Cardiol 1997; 30: 91-96.
• 105 Koh KK. Effects of HMG-CoA reductase inhibitor on hemostasis. Int J Cardiol 2000; 76: 23-32.
• 106 Puccetti L, Pasqui AL, Pastorelli M. et al. Platelet hyperactivity after statin treatment discontinuation. Thromb Haemost 2003; 90: 476-82.
• 107 Mussoni L, Banfi C, Sironi L. et al. Fluvastatin inhibits basal and stimulated plasminogen activator inhibitor 1, but induces tissue type plasminogen activator in cultured human endothelial cells. Thromb Haemost 2000; 84: 59-64.
• 108 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: 556-62.
• 109 Isaacsohn JL, Setaro JF, Nicholas C. et al. Effects of lovastatin therapy on plasminogen activator inhibitor-1 antigen levels. Am J Cardiol 1997; 74: 735-7.
• 110 Bevilacqua M, Bettica P, Milani M. et al. Effect of fluvastatin on lipids and fibrinolysis in coronary artery disease. Am J Cardiol 1997; 79: 84-7.
• 111 Wiesbauer F, Kaun C, Zorn G. et al. HMGCoA reductase inhibitors affect the fibrinolytic system of human vascular cells in vitro: a comparative study using different statins. Br J Pharmacol 2002; 135: 284-92.
• 112 Dangas G, Smith DA, Unger AH. et al. Pravastatin: an antithrombotic effect independent of the cholesterol-lowering effect. Thromb Haemost 2000; 83: 688-92.
• 113 Seljeflot I, Tonstad S, Hjermann I. et al. Reduced expression of endothelial cell markers after 1 year treatment with simvastatin and atorvastatin in patients with coronary heart disease. Atherosclerosis 2002; 162: 179-85.
• 114 Kwak B, Mulhaupt F, Myit S. et al. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 06: 1399-402.
• 115 Hakamada-Taguchi R, Uehara Y, Kuribayashi K. et al. Inhibition of hydroxymethylglutaryl-coenzyme A reductase reduces Th1 development and promotes Th2 development. Circ Res 2003; 93: 948-56.
• 116 Blanco-Colio LM, Munoz-Garcia B, Martin-Ventura JL. et al. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition decrease Fas ligand expression and cytotoxity inactivated human T lymphocytes. Circulation 2003; 108: 1506-13.
• 117 Sherer Y, Shoenfeld Y. Immunomodulation for treatment and prevention of atherosclerosis. Autoimmun Rev 2002; 01: 21-7.
• 118 Mach F. Statins as novel immunomodulators: from cell to potential clinical benefit. Thromb Haemost 2003; 90: 607-10.
• 119 Chen Z, Fukutomi T, Zago AC. et al. Simvastatin reduces neointimal thickening in lowdensity lipoprotein receptor-deficient mice after experimental angioplasty without changing plasma lipids. Circulation 2002; 106: 20-23.
• 120 Vincent L, Albanese P, Bompais H. et al. Insights in the molecular mechanisms of the anti-angiogenic effect of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Thromb Haemost 2003; 89: 530-7.
• 121 Frick M, Dulak J, Cisowski J. et al. Statins differentially regulate vascular endothelial growth factor synthesis in endothelial and vascular smooth muscle cells. Atherosclerosis 2003; 170: 229-36.
• 122 Franz HAlber, Dulak J, Frick M. et al. Atorvastatin decreases vascular endothelial growth factor in patients with coronary artery disease. J Am Coll Cardiol 2002; 39: 1951-5.
• 123 Blann AD, Belgore FM, Constans J. et al. Plasma vascular endothelial growth factor and its receptor FLt-1 in patients with hyperlipidemia and atherosclerosis and the effects of fluvastatin or fenofibrate. Am J Cardiol 2001; 87: 1160-3.
• 124 Porati I, Kimmelstiel C, Rand W. et al. Statins use is associated with enhanced collateralization of severely diseased coronary arteries. Am Heart J 2003; 146: 876-81.
• 125 Skaletz-Rorowski A, Walsh K. Statin therapy and angiogenesis. Curr Opin Lipidol 2003; 14: 599-603.
• 126 Vasa M, Fichtlscherer S, Adler K. et al. Increase in endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001; 103: 2885-90.
• 127 Dimmeler S, Aicher A, Vasa M. et al. HMGCoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI3-kinase/Akt-pathway. J Clin Invest 2001; 108: 391-7.
• 128 Assmus B, Urbich C, Aicher A. et al. HMGCoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulation genes. Circ Res 2003; 92: 1049-55.
• 129 Bonetti PO, Lerman LO, Napoli C. et al. Statin effects beyond lipid lowering – are they clinically relevant?. Eur Heart J 2003; 24: 225-48.
• 130 De Backer G, Ambrosioni E, Borch-Johnsen K. et al. Executive summary. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force and other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 2003; 24: 1601-10.
• 131 Anonymous 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.
• 132 Pitt B, Waters D, Brown WV. et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999; 341: 70-6.
• 133 Schwartz GG, Olsson AG, Ezekowitz MD. et al. Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled study. JAMA 2001; 285: 1711-8.
• 134 McKoewn B, Thompson PL. Early initiation of statin therapy after a coronary event. Curr Opin Lipidol 2002; 13: 631-5.
• 135 Walter DH, Schachinger V, Elsner M. et al. Effect of statin therapy on restenosis after coronary stent implantation. Am J Cardiol 2000; 85: 962-8.
• 136 Weintraub WS, Boccuzzi SJ, Klein JL. et al. Lack of effect of lovastatin on restenosis after coronary angioplasty: Lovastatin Restenosis Trial Study Group. N Engl J Med 1994; 331: 1331-7.
• 137 Horne BD, Muhlestein JB, Carlquist JF. et al. Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease. J Am Coll Cardiol 2000; 36: 1774-80.
• 138 Walter DH, Fichtlscherer S, Britten MB. et al. Statin therapy, inflammation and recurrent coronary events in patients following coronary stent implantation. J Am Coll Cardiol 2001; 38: 2006-12.
• 139 Ray JG, Mamdani M, Tsuyaki RT. et al. Use of statins and the subsequent development of deep vein thrombosis. Arch Intern Med 2001; 161: 1405-10.