Statins Effect on Smooth Muscle Cell Proliferation

ABSTRACT

Clinical trials have firmly established that 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors (statins) can induce regression of vascular atherosclerosis as well as reduction of cardiovascular-related morbidity and death in patients with and without coronary artery disease. These beneficial effects of statins are usually assumed to result from their ability to reduce cholesterol synthesis. However, because mevalonic acid is the precursor not only of cholesterol but also of many nonsteroidal isoprenoid compounds, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase may result in pleiotropic effects. Indeed, statins can interfere with major events involved in the formation and the evolution of atherosclerotic lesions, such as arterial myocyte migration and proliferation and cholesterol accumulation, independent of their hypolipidemic properties. The aim of this article is to focus on clinical and experimental data that show that statins possess effects beyond cholesterol lowering, particularly on arterial smooth muscle cell proliferation. The contribution of these direct vascular effects to the reduction of cardiovascular events observed in clinical trials with statins represents one of the major challenges for future studies to understand the antiatherosclerotic benefits of these agents.

KEYWORDS

HMG-CoA reductase inhibitors - atherosclerosis - cell growth - statin - hypolipidemic drugs

REFERENCES

• 1 Grundy S M, Cleeman J I, Merz C N et al.. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.  Circulation. 2004;  110 227-239
• 2 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults . Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).  JAMA. 2001;  285 2486-2497
• 3 Prevention of coronary heart disease in clinical practice . Recommendations of the Second Joint Task Force of European and other Societies on coronary prevention.  Eur Heart J. 1998;  19 1434-1503
• 4 Scott L J, Curran M P, Figgitt D P. Rosuvastatin: a review of its use in the management of dyslipidemia.  Am J Cardiovasc Drugs. 2004;  4 117-138
• 5 McTaggart F, Buckett L, Davidson R et al.. Preclinical and clinical pharmacology of Rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.  Am J Cardiol. 2001;  87 28B-32B
• 6 Corsini A, Bellosta S, Baetta R et al.. New insights into the pharmacodynamic and pharmacokinetic properties of statins.  Pharmacol Ther. 1999;  84 413-428
• 7 Bellosta S, Paoletti R, Corsini A. History and development of HMG-CoA reductase inhibitors. In: Schmitz G, Torzewski M HMG-CoA Reductase Inhibitors. Basel; Birkhauser 2002: 1-17
• 8 Goldstein J L, Brown M S. Regulation of the mevalonate pathway.  Nature. 1990;  343 425-430
• 9 Maltese W A. Posttranslational modification of proteins by isoprenoids in mammalian cells.  FASEB J. 1990;  4 3319-3328
• 10 Glomset J A, Gelb M H, Farnsworth C C. Prenyl proteins in eukaryotic cells: a new type of membrane anchor.  Trends Biochem Sci. 1990;  15 139-142
• 11 Laufs U, Liao J K. Isoprenoid metabolism and the pleiotropic effects of statins.  Curr Atheroscler Rep. 2003;  5 372-378
• 12 Davignon J. Beneficial cardiovascular pleiotropic effects of statins.  Circulation. 2004;  109 III39-III43
• 13 Nakai D, Nakagomi R, Furuta Y et al.. Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes.  J Pharmacol Exp Ther. 2001;  297 861-867
• 14 Komai T, Shigehara E, Tokui T et al.. Carrier-mediated uptake of pravastatin by rat hepatocytes in primary culture.  Biochem Pharmacol. 1992;  43 667-670
• 15 Shaw M K, Newton R S, Sliskovic D R et al.. Hep-G2 cells and primary rat hepatocytes differ in their response to inhibitors of HMG-CoA reductase.  Biochem Biophys Res Commun. 1990;  170 726-734
• 16 Ross R. Atherosclerosis-an inflammatory disease.  N Engl J Med. 1999;  340 115-126
• 17 Pickering J G, Weir L, Jekanowski J, Kearney M A, Isner J M. Proliferative activity in peripheral and coronary atherosclerotic plaque among patients undergoing percutaneous revascularization.  J Clin Invest. 1993;  91 1469-1480
• 18 Gordon D, Reidy M A, Benditt E P, Schwartz S M. Cell proliferation in human coronary arteries.  Proc Natl Acad Sci USA. 1990;  87 4600-4604
• 19 Miller M J, Kuntz R E, Friedrich S P et al.. Frequency and consequences of intimal hyperplasia in specimens retrieved by directional atherectomy of native primary coronary artery stenoses and subsequent restenoses.  Am J Cardiol. 1993;  71 652-658
• 20 O'Brien E R, Alpers C E, Stewart D K et al.. Proliferation in primary and restenotic coronary atherectomy tissue. Implications for antiproliferative therapy.  Circ Res. 1993;  73 223-231
• 21 Jackson C L, Schwartz S M. Pharmacology of smooth muscle cell replication.  Hypertension. 1992;  20 713-736
• 22 Ip J H, Fuster V, Badimon L et al.. Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation.  J Am Coll Cardiol. 1990;  15 1667-1687
• 23 Bellosta S, Bernini F, Ferri N et al.. Direct vascular effects of HMG-CoA reductase inhibitors.  Atherosclerosis. 1998;  137(Suppl) S101-S109
• 24 Glomset J A, Farnsworth C C. Role of protein modification reactions in programming interactions between ras-related GTPases and cell membranes.  Annu Rev Cell Biol. 1994;  10 181-205
• 25 Farnsworth C C, Wolda S L, Gelb M H, Glomset J A. Human lamin B contains a farnesylated cysteine residue.  J Biol Chem. 1989;  264 20422-20429
• 26 Raiteri M, Arnaboldi L, McGeady P et al.. Pharmacological control of the mevalonate pathway: effect on arterial smooth muscle cell proliferation.  J Pharmacol Exp Ther. 1997;  281 1144-1153
• 27 Soma M R, Donetti E, Parolini C et al.. HMG CoA reductase inhibitors. In vivo effects on carotid intimal thickening in normocholesterolemic rabbits.  Arterioscler Thromb. 1993;  13 571-578
• 28 Soma M R, Parolini C, Donetti E, Fumagalli R, Paoletti R. Inhibition of isoprenoid biosynthesis and arterial smooth-muscle cell proliferation.  J Cardiovasc Pharmacol. 1995;  25(Suppl 4) S20-S24
• 29 Bocan T M, Mazur M J, Mueller S B et al.. Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterol-fed rabbits: a biochemical and morphological evaluation.  Atherosclerosis. 1994;  111 127-142
• 30 Gellman J, Ezekowitz M D, Sarembock I J et al.. Effect of lovastatin on intimal hyperplasia after balloon angioplasty: a study in an atherosclerotic hypercholesterolemic rabbit.  J Am Coll Cardiol. 1991;  17 251-259
• 31 Zhu B Q, Sievers R E, Sun Y P, Isenberg W M, Parmley W W. Effect of lovastatin on suppression and regression of atherosclerosis in lipid-fed rabbits.  J Cardiovasc Pharmacol. 1992;  19 246-255
• 32 Bandoh T, Mitani H, Niihashi M et al.. Inhibitory effect of fluvastatin at doses insufficient to lower serum lipids on the catheter-induced thickening of intima in rabbit femoral artery.  Eur J Pharmacol. 1996;  315 37-42
• 33 Igarashi M, Takeda Y, Mori S et al.. Suppression of neointimal thickening by a newly developed HMG-CoA reductase inhibitor, BAYw6228, and its inhibitory effect on vascular smooth muscle cell growth.  Br J Pharmacol. 1997;  120 1172-1178
• 34 Veinot J P, Edwards W D, Camrud A R et al.. The effects of lovastatin on neointimal hyperplasia following injury in a porcine coronary artery model.  Can J Cardiol. 1996;  12 65-70
• 35 Corsini A, Pazzucconi F, Arnaboldi L et al.. Direct effects of statins on the vascular wall.  J Cardiovasc Pharmacol. 1998;  31 773-778
• 36 Corsini A, Pazzucconi F, Pfister P, Paoletti R, Sirtori C R. Inhibitor of proliferation of arterial smooth-muscle cells by fluvastatin.  Lancet. 1996;  348 1584
• 37 Tse F L, Jaffe J M, Troendle A. Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers.  J Clin Pharmacol. 1992;  32 630-638
• 38 Maltese W A, Defendini R, Green R A, Sheridan K M, Donley D K. Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.  J Clin Invest. 1985;  76 1748-1754
• 39 Soma M R, Baetta R, De Renzis M R et al.. In vivo enhanced antitumor activity of carmustine [N,N′-bis(2-chloroethyl)-N-nitrosourea] by simvastatin.  Cancer Res. 1995;  55 597-602
• 40 Bernini F, Didoni G, Bonfadini G, Bellosta S, Fumagalli R. Requirement for mevalonate in acetylated LDL induction of cholesterol esterification in macrophages.  Atherosclerosis. 1993;  104 19-26
• 41 Comparato C, Altana C, Bellosta S et al.. Clinically relevant pleiotropic effects of statins: drug properties or effects of profound cholesterol reduction?.  Nutr Metab Cardiovasc Dis. 2001;  11 328-343
• 42 Mintz G S, Popma J J, Pichard A D et al.. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study.  Circulation. 1996;  94 35-43
• 43 Scheller B, Schmitt A, Bohm M, Nickenig G. Atorvastatin stent coating does not reduce neointimal proliferation after coronary stenting.  Z Kardiol. 2003;  92 1025-1028
• 44 Farb A, Sangiorgi G, Carter A J et al.. Pathology of acute and chronic coronary stenting in humans.  Circulation. 1999;  99 44-52
• 45 Walter D H, Schachinger V, Elsner M et al.. Effect of statin therapy on restenosis after coronary stent implantation.  Am J Cardiol. 2000;  85 962-968
• 46 Serruys P W, Foley D P, Jackson G et al.. A randomized placebo-controlled trial of fluvastatin for prevention of restenosis after successful coronary balloon angioplasty; final results of the fluvastatin angiographic restenosis (FLARE) trial.  Eur Heart J. 1999;  20 58-69
• 47 Bertrand M E, McFadden E P, Fruchart J C et al.. Effect of pravastatin on angiographic restenosis after coronary balloon angioplasty. The PREDICT Trial Investigators. Prevention of Restenosis by Elisor after Transluminal Coronary Angioplasty.  J Am Coll Cardiol. 1997;  30 863-869
• 48 Weintraub W S, Boccuzzi S J, Klein J L et al.. Lack of effect of lovastatin on restenosis after coronary angioplasty. Lovastatin Restenosis Trial Study Group.  N Engl J Med. 1994;  331 1331-1337
• 49 Serruys P W, de Feyter P, Macaya C et al.. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.  JAMA. 2002;  287 3215-3222
• 50 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
• 51 Sata M, Nishimatsu H, Osuga J et al.. Statins augment collateral growth in response to ischemia but they do not promote cancer and atherosclerosis.  Hypertension. 2004;  43 1214-1220
• 52 Ridker P M, Rifai N, Pfeffer M A, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators.  Circulation. 1999;  100 230-235
• 53 Sparrow C P, Burton C A, Hernandez M et al.. Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering.  Arterioscler Thromb Vasc Biol. 2001;  21 115-121
• 54 Romano M, Diomede L, Sironi M et al.. Inhibition of monocyte chemotactic protein-1 synthesis by statins.  Lab Invest. 2000;  80 1095-1100
• 55 Kimura M, Kurose I, Russell J, Granger D N. Effects of fluvastatin on leukocyte-endothelial cell adhesion in hypercholesterolemic rats.  Arterioscler Thromb Vasc Biol. 1997;  17 1521-1526
• 56 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