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Inicio Clínica e Investigación en Arteriosclerosis Efectos inmunomoduladores de las estatinas
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Vol. 17. Núm. S2.
Efectos pleiotrópicos de las estatinas
Páginas 1-8 (Septiembre 2005)
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Vol. 17. Núm. S2.
Efectos pleiotrópicos de las estatinas
Páginas 1-8 (Septiembre 2005)
Efectos pleiotrópicos de las estatinas
Acceso a texto completo
Efectos inmunomoduladores de las estatinas
Immunomodulatory effects of statins
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561
X. Pintó
Autor para correspondencia
xpinto@csub.scs.es

Correspondencia: Dr. X. Pintó. Unidad de Lípidos y Arteriosclerosis. Servicio de Medicina Interna. Hospital Universitario de Bellvitge. Feixa Llarga, s/n. 08907 L’Hospitalet de Llobregat. Barcelona. España.
Unidad de Lípidos y Arteriosclerosis. Servicio de Medicina Interna. Hospital Universitario de Bellvitge. L’Hospitalet de Llobregat. Barcelona. España
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Las estatinas actúan sobre la síntesis del colesterol, pero también de otras moléculas derivadas del mevalonato relacionadas con la respuesta inmunológica, entre ellas los isoprenoides farnesil y geranilgeranil pirofosfato, que intervienen en la señalización intracelular de respuestas inflamatorias reguladas por las proteínas Ras y Rho. Las estatinas disminuyen la expresión de CD-40 en las células endoteliales y los monocitos de la pared arterial, inhiben la adhesión y la coestimulación de los linfocitos mediada por el antígeno de función leucocitaria, disminuyen la expresión de las moléculas principales del antígeno de histocompatibilidad de clase II y la maduración y la función presentadora de antígenos de las células dendríticas. Estos fármacos se utilizan en la actualidad de manera sistemática en los pacientes con trasplantes cardíacos y su prescripción probablemente aumentará en los próximos años en los pacientes con trasplante de otros órganos. Las estatinas podrían considerarse en la terapia de otras enfermedades de base inmunológica, como la artritis reumatoide y la esclerosis múltiple, el cáncer y las enfermedades infecciosas. En el presente artículo se revisan las evidencias sobre estos aspectos que han aportado los estudios experimentales, clínicos y epidemiológicos.

Palabras clave:
Estatinas
Inmunidad
Cáncer
Trasplante de órganos
Sepsis
Sida
Artritis reumatoide

Statins act on cholesterol synthesis, as well as on the synthesis of other mevalonate-derived molecules involved in immune response; among these are the isoprenoids, farnesil and geranylgeranyl pyrophosphate, which intervene in intracellular signaling of inflammatory responses regulated by the proteins Ras and Rho. Statins decrease CD-40 expression in endothelial cells and monocytes of the arterial wall, inhibit adhesion and co-stimulation of lymphocytes mediated by leukocyte function antigen, decrease expression of the principal class II histocompatibility antigen molecules, and the maturation and antigen-presenting function of dendritic cells. Currently, these drugs are routinely used in cardiac transplant recipients and their prescription will probably increase in the next few years in patients undergoing transplantation of other organs. Statins could be considered in the therapy of other diseases with an immunologic basis, such as rheumatoid arthritis, multiple sclerosis, cancer, and infectious diseases. The present article reviews the evidence on these features provided by experimental, clinical, and epidemiological studies.

Key words:
Statins
Immunity
Cancer
Organ transplantation
Sepsis
AIDS
Rheumatoid arthritis
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Bibliografía
[1.]
R. Paoletti, A.M. Gotto, D.P. Hajjar.
Inflammation in atherosclerosis and implications for therapy.
Circulation, 109 (2004), pp. 20-26
[2.]
G.K. Hansson.
Inflammation, atherosclerosis, and coronary artery disease.
N Engl J Med, 352 (2005), pp. 1685-1695
[3.]
J.L. Goldstein, M.S. Brown.
Regulation of the mevalonate pathway.
Nature, 343 (1990), pp. 425-430
[4.]
J. Banchereau, F. Briere, C. Caux, J. Davoust, S. Lebecque, Y.J. Liu, et al.
Immunobiology of dendritic cells.
Annu Rev Immunol, 18 (2000), pp. 767-811
[5.]
I. Jialal, D. Stein, D. Balis, S.M. Grundy, B. Adams-Huet, S. Devaraj.
Effect of hydroymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels.
Circulation, 103 (2001), pp. 1933-1935
[6.]
S.E. Nissen, E.M. Tuzcu, P. Schoenhagen, T. Crowe, W.J. Sasiela, J. Tsai, et al.
Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) Investigators. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease.
N Engl J Med, 352 (2005), pp. 29-38
[7.]
P.M. Ridker, C.P. Cannon, D. Morrow, N. Rifai, L.M. Rose, C.H. McCabe, et al.
Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE ITTIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy.
N Engl J Med, 352 (2005), pp. 20-28
[8.]
A.H. Wagner, M. Gebauer, B. Guldenzoph, M. Hecker.
3-hydroxy-3- methylglutaryl coenzyme A reductase-independent inhibition of CD40 expression by atorvastatin in human endothelial cells.
Arterioscler Thromb Vasc Biol, 22 (2002), pp. 1784-1789
[9.]
G. Weitz-Schmidt, K. Welzenbach, V. Brinkmann, T. Kamata, J. Kallen, C. Bruns, et al.
Statins selectively inhibit leukocyte function antigen-1 by binding to a novel integrin site.
Nat Med, 7 (2001), pp. 687-692
[10.]
B. Kwak, F. Mulhaupt, S. Myit, F. Mach.
Statins as a newly recognized type of immunomodulator.
Nat Med, 6 (2000), pp. 1399-1402
[11.]
F. Mach.
Statins as immunomodulatory agents.
Circulation, 109 (2004), pp. 15-17
[12.]
A. Yilmaz, C. Reiss, O. Tantawi, A. Weng, C. Stumpf, D. Raaz, et al.
HMGCoA reductase inhibitors supress maturation of human dendritic cells: new implications for atherosclerosis.
Atherosclerosis, 172 (2004), pp. 85-93
[13.]
M.R. Graaf, A.B. Beiderbeck, A.C.G. Egberts, D.J. Richel, H.J. Guchelaar.
The risk of cancer in users of statins.
J Clin Oncol, 22 (2004), pp. 2388-2394
[14.]
M.R. Graaf, D.J. Richel, C.J. Van Noorden, H.J. Guchelaar.
Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer.
Cancer Treat Rev, 30 (2004), pp. 609-641
[15.]
P.R. Hebert, J.M. Gaziano, K.S. Chan, C.H. Hennekens.
Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials.
JAMA, 278 (1997), pp. 313-321
[16.]
L.M. Bjerre, J. LeLorier.
Do statins cause cancer? A meta-analysis of large randomized clinical trials.
Am J Med, 110 (2001), pp. 716-723
[17.]
M.A. Pfeffer, A. Keech, F.M. Sacks, S.M. Cobbe, A. Tonkin, R.P. Byington, et al.
Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling (PPP) Project.
Circulation, 105 (2002), pp. 2341-2346
[18.]
L. Blais, A. Desgagne, J. LeLorier.
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer: a nested case-control study.
Arch Intern Med, 160 (2000), pp. 2363-2368
[19.]
J.A. Kaye, H. Jick.
Statin use and cancer risk in the General Practice Research Database.
Br J Cancer, 90 (2004), pp. 635-637
[20.]
M.R. Graaf, A.B. Beiderbeck, A.C. Egberts, D.J. Richel, H.J. Guchelaar.
The risk of cancer in users of statins.
J Clin Oncol, 22 (2004), pp. 2388-2394
[21.]
J.N. Poynter, S.B. Gruber, P.D. Higgins, R. Almog, J.D. Bonner, H.S. Rennert, et al.
Statins and the risk of colorectal cancer.
N Engl J Med, 352 (2005), pp. 2184-2192
[22.]
T. Narisawa, Y. Fukaura, K. Terada, A. Umezawa, N. Tanida, K. Yazawa, et al.
Prevention of 1,2-dimethylhydrazine-induced colon tumorigenesis by HMG-CoA reductase inhibitors, pravastatin and simvastatin, in ICR mice.
Carcinogenesis, 15 (1994), pp. 2045-2048
[23.]
B.P. Leung, N. Sattar, A. Crilly, M. Prach, D.W. McCarey, H. Payne, et al.
A novel anti-inflammatory role for simvastatin in inflammatory arthritis.
J Immunol, 170 (2003), pp. 1524-1530
[24.]
D.W. McCarey, I.B. McInnes, R. Madhok, R. Hampson, O. Scherbakor, I. Ford, et al.
Trial of Atorvastatin in Rheumatoid Arthritis (TARA): doubleblind, randomised placebo-controlled trial.
Lancet, 363 (2004), pp. 2015-2021
[25.]
T. Vollmer, L. Key, V. Durkalski, W. Tyor, J. Corboy, S. Markovic-Plese, et al.
Oral simvastatin treatment in relapsing-remitting multiple sclerosis.
Lancet, 363 (2004), pp. 1607-1608
[26.]
S.A. Rizvi, K. Bashir.
Other therapy options and future strategies for tretaing patients with multiple sclerosis.
Neurology, 63 (2004), pp. 47-54
[27.]
J. Kallen, K. Welzenbach, P. Ramage, D. Geyl, R. Kriwacki, G. Legge, et al.
Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a 1-domain.
J Mol Biol, 292 (1999), pp. 1-9
[28.]
S. Bounou, J.E. Leclerc, M.J. Tremblay.
Presence of host ICAM-1 in laboratory and clinical strains of human immunodeficiency virus type 1 increases virus infectivity and CD4(+)-T-cell depletion in human lymphoid tissue, a major site of replication in vivo.
J Virol, 76 (2002), pp. 1004-1014
[29.]
J.F. Giguere, M.J. Tremblay.
Statin compounds reduce human immunodeficiency virus type 1 replication by preventing the interaction between virion-associated host intercellular adhesion molecule 1 and its natural cell surface ligand LFA-1.
[30.]
G. Weitz-Schmidt, K. Welzenbach, V. Brinkmann, T. Kamata, J. Kallen, C. Bruns, et al.
Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site.
Nat Med, 7 (2001), pp. 687-692
[31.]
G. Del Real, S. Jiménez-Baranda, E. Mira, R.A. Lacalle, P. Lucas, C. Gómez-Mouton, et al.
Statins inhibit HIV-1 infection by down-regulating Rho activity.
J Exp Med, 200 (2004), pp. 541-547
[32.]
A.P. Liappis, V.L. Kan, C.G. Rochester, G.L. Simon.
The effect of statins on mortality in patients with bacteremia.
Clin Infect Dis, 33 (2001), pp. 1352-1357
[33.]
Y. Almog, A. Shefer, V. Novack, et al.
Prior statin therapy is associated with a decreased rate of severe sepsis.
Circulation, 110 (2004), pp. 880-885
[34.]
S. Steiner, W.S. Speidl, J. Pleiner.
Simvastatin blunts endotoxin-induced tissue factor in vivo.
Circulation, 111 (2005), pp. 1841-1846
[35.]
I. Zelvyte, R. Dominaitiene, M. Crisby, S. Janciauskiene.
Modulation of inflammatory mediators and PPARgamma and NFkappaB expression by pravastatin in response to lipoproteins in human monocytes in vitro.
Pharmacol Res, 45 (2002), pp. 147-154
[36.]
H. Holdaas, B. Fellstrom, A.G. Jardine, I. Holme, G. Nyberg, P. Fauchald, et al.
Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial.
Lancet, 361 (2003), pp. 2024-2031
[37.]
B. Fellstrom, A.G. Jardine, I. Soveri, E. Cole, C. Gronhagen-Riska, H.H. Newmayer, et al.
Renal dysfunction as a risk factor for mortality and cardiovascular disease in renal transplantation: experience from the Assessment of Lescol in Renal Transplantation trial.
Transplantation, 79 (2005), pp. 1160-1163
[38.]
C.M. Ballantyne, E.J. Podet, W.P. Patsch, Y. Harati, V. Appel, A.M. Gotto Jr, J.B. Young.
Effects of cyclosporine therapy on plasma lipoprotein levels.
JAMA, 262I 1 (1989), pp. 53-56
[39.]
J.A. Kobashigawa, B.L. Kasiske.
Hyperlipidemia in solid organ transplantation.
Transplantation, 63 (1997), pp. 331-338
[40.]
K.C. Bilchick, C.A. Henrikson, D. Skojec, E.K. Kasper, R.S. Blumenthal.
Treatment of hyperlipidemia in cardiac transplant recipients.
Am Heart J, 148 (2004), pp. 200-210
[41.]
J.A. Kobashigawa, S. Katznelson, H. Laks, J.A. Johnson, L. Yeatman, X.M. Wang, et al.
Effect of pravastatin on outcomes after cardiac transplantation.
N Engl J Med, 33 (1995), pp. 621-627
[42.]
K. Wenke, B. Meiser, J. Thiery, D. Nagel, W. Von Scheidt, K. Krobot, et al.
Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial.
Circulation, 96 (1997), pp. 1398-1402
[43.]
K. Wenke, B. Meiser, J. Thiery, D. Nagel, W. Von Scheidt, K. Krobot, et al.
Simvastatin initiated early after heart transplantation: 8-year prospective experience.
Circulation, 107 (2003), pp. 93-97
[44.]
M.R. Mehra, P.A. Uber, K. Vivekananthan, S. Solis, R.L. Scott, M.H. Park, et al.
Comparative beneficial effects of simvastatin and pravastatin on cardiac allograft rejection and survival.
J Am Coll Cardiol, 40 (2002), pp. 1609-1614
[45.]
G. Magnani, V. Carinci, C. Magelli, L. Potena, L.B. Reggiani, A. Branzi.
Role of statins in the management of dyslipidemia after cardiac transplant: randomized controlled trial comparing the efficacy and the safety of atorvastatin with pravastatin.
J Heart Lung Transplant, 19 (2000), pp. 710-715
[46.]
P.J. Taylor, P.A. Kubler, S.V. Lynch, J. Allen, M. Butler, P.I. Pillans.
Effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients.
Ann Pharmacother, 38 (2004), pp. 205-208
[47.]
L.W. Miller, R.C. Schlant, J. Kobashigawa, S. Kubo, D.G. Renlund.
24th Bethesda conference: Cardiac transplantation. Task Force 5: Complications.
J Am Coll Cardiol, 22 (1993), pp. 41-54
[48.]
B.A. Johnson, A.T. Iacono, A. Zeevi, K.R. McCurry, S.R. Duncan.
Statin use is associated with improved function and survival of lung allografts.
Am J Respir Crit Care Med, 167 (2003), pp. 1271-1278
Copyright © 2005. Sociedad Española de Arteriosclerosis y Elsevier España S.L.
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