Buscar en
Clínica e Investigación en Arteriosclerosis
Toda la web
Inicio Clínica e Investigación en Arteriosclerosis ¿Actúan las estatinas a través de los PPARα?
Información de la revista
Vol. 17. Núm. S2.
Efectos pleiotrópicos de las estatinas
Páginas 9-14 (Septiembre 2005)
Compartir
Compartir
Descargar PDF
Más opciones de artículo
Vol. 17. Núm. S2.
Efectos pleiotrópicos de las estatinas
Páginas 9-14 (Septiembre 2005)
Efectos pleiotrópicos de las estatinas
Acceso a texto completo
¿Actúan las estatinas a través de los PPARα?
Do statins act through PPARα?
Visitas
256
J.C. Laguna
Autor para correspondencia
jclagunae@ub.edu

Correspondencia: Dr. J.C. Laguna. Unidad de Farmacología y Farmacognosia. Facultad de Farmacia. Universidad de Barcelona. Avda. Diagonal, 643. 08028 Barcelona. España.
Unidad de Farmacología y Farmacognosia. Facultad de Farmacia. Universidad de Barcelona. Barcelona. España
Este artículo ha recibido
Información del artículo

Los inhibidores de la hidroximetilglutaril-CoA reductasa, o estatinas, y los derivados del ácido fíbrico (fibratos) son las dos familias de fármacos más ampliamente utilizadas en el tratamiento de las dislipemias. Tanto las estatinas como los fibratos producen efectos beneficiosos superiores a los esperables a partir de la modificación de las concentraciones de lípidos plasmáticos inducida por el tratamiento. Estos efectos, denominados de forma genérica como efectos pleiotrópicos, son de naturaleza mayoritariamente antiinflamatoria y, muchos de ellos, comunes a fibratos y estatinas. En la presente revisión se discute la posible convergencia en las vías moleculares de producción de los efectos pleiotrópicos de los fibratos y las estatinas, a través de la modulación de la actividad transcripcional de PPARα y NF-κB.

Palabras clave:
Estatinas
PPAR
NF-κB
Efectos pleieotrópicos

Hydroxymethylglutaryl-CoA reductase inhibitors, or statins, and fibric acid derivatives, or fibrates, are the two most widely used drug families in the treatment of dyslipidemias. Both statins and fibrates produce beneficial effects that go beyond those that could be expected on the basis of the modification of plasma lipid concentrations produced by the treatment. These effects, known generically as pleiotropic effects, are mainly anti-inflammatory and many of them are common to fibrates and statins. The present review discusses the possible convergence in the molecular pathways producing the pleiotropic effects of fibrates and statins through modulation of the transcriptional activity of PPARα and nuclear factor-κβ.

Key words:
Statins
PPAR
NF-κB
Pleieotropic effects
El Texto completo está disponible en PDF
Bibliografía
[1.]
J.K. Liao, U. Laufs.
Pleiotropic effects of statins.
Annu Rev Pharmacol Toxicol, 45 (2005), pp. 89-118
[2.]
R.M. Sánchez, J.C. Laguna.
Nuevos mecanismos moleculares de la atorvastatina.
Clin Invest Arterioscl, 1 (2003), pp. 3-14
[3.]
L. Van Aelst, C. D'Souza-Schorey.
Rho GTP-ases and signaling networks.
Genes Dev, 11 (1997), pp. 2295-2322
[4.]
J.K. Liao.
Isoprenoids as mediators of the biological effects of statins.
J Clin Invest, 110 (2002), pp. 285-288
[5.]
M. Essig, G. Nguyen, D. Prie, B. Escoubet, J.D. Sraer, G. Friedlander.
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranyl-geranylation and Rho proteins.
Circ Res, 83 (1998), pp. 490-500
[6.]
O. Hernández-Perera, D. Pérez-Sala, E. Soria, S. Lamas.
Involvement of Rho GTPasas in the transcriptional inhibition of preendothelin-1 gene expression by simvastatin in vascular endothelial cells.
Circ Res, 87 (2000), pp. 616-622
[7.]
R. Singh, B. Wang, A. Shirvaikar, S. Khan, S. Kamat, J.R. Scehlling, et al.
The IL-1 receptor and Rho directly associate to drive cell activation in inflammation.
J Clin Invest, 103 (1999), pp. 1561-1570
[8.]
G. Mundy, R. Garret, S. Harris, J. Chan, D. Chen, G. Rossini, et al.
Stimulation of bone formation in vitro and in rodents by statins.
Science, 286 (1999), pp. 1946-1949
[9.]
R.H. Bloomfield, J. Davenport, V. Babikian, L.M. Brass, D. Collins, L. Wexler, et al.
Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT).
Circulation, 103 (2001), pp. 2828-2833
[10.]
G. Ruotolo, C.G. Ericsson, C. Tettamanti, F. Karpe, L. Grip, B. Svane, et al.
Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT).
J Am Coll Cardiol, 32 (1998), pp. 1648-1656
[11.]
H.B. Rubins, S.J. Robins.
Conclusions from the VA-HIT study.
Am J Cardiol, 86 (2000), pp. 543-544
[12.]
J.C. Laguna.
PPAR e inflamación.
Lípidos, arteriosclerosis y factores de riesgo no convencionales, pp. 149-161
[13.]
D.H. Van Raalte, M. Li, H. Pritchard, K.M. Wasan.
Peroxisome proliferator-activated receptor (PPAR)α: a pharmacological target with a promising future.
Pharm Res, 21 (2004), pp. 1531-1538
[14.]
J.P. Després, I. Lemieux, S.J. Robins.
Role of fibric acid derivatives in the management of risk factors for coronary heart disease.
[15.]
M. Iglarz, V. Touyz, D. Wichterle, M.F. Lavoie, Q.F. Diep, E.L. Schiffrin.
Effect of peroxisome proliferator-activated receptor-alpha and-gamma activators on vascular remodelling in endothelin-dependent hypertension.
Arterioscler Thromb Vasc Biol, 23 (2003), pp. 45-51
[16.]
N. Marx, G.K. Sukhova, T. Collins, P. Libby, J. Plutzky.
PPAR-alpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells.
Circulation, 99 (1999), pp. 3125-3131
[17.]
C. Weber, W. Erl, K.S. Weber, P.C. Weber.
HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia.
J Am Coll Cardiol, 30 (1997), pp. 1212-1217
[18.]
B. Staels, W. Koenig, A. Habib, R. Merval, M. Lebret, I. Pineda-Torra, et al.
Activation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activators.
Nature, 393 (1998), pp. 790-793
[19.]
A. Rezaie-Majd, T. Maca, R.A. Bucek, P. Valent, R.M. Muller, P. Husslein, et al.
Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients.
Arterioscl Thromb Vasc Biol, 22 (2002), pp. 1194-1199
[20.]
A. Madej, B. Okopien, J. Kowalski, M. Zielinski, J. Wysocki, B. Szygula, et al.
Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia IIb.
Int J Clin Pharmacol Ther, 36 (1998), pp. 345-349
[21.]
P.M. Ridker, N. Rifai, M. Cleafield, J.R. Downs, S.E. Weis, J.S. Miles, et al.
Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events.
N Engl J Med, 344 (2001), pp. 1959-1965
[22.]
N. Roglans, C. Peris, J.C. Verd, T. Adzet, M. Alegret, M. Vázquez, et al.
Increase in hepatic expression of SREBP-2 by gemfibrozil administration to rats.
Biochem Pharmacol, 62 (2001), pp. 803-809
[23.]
S.G. Inoue, K. Mizotani, T. Awata, T. Mastunaga, S. Kawai, S.H. Nakajima, et al.
Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect. reduction of mRNA levels of interleukin-1β, interleukin-6, cicloxygenase-2 and p22phox by regulation of peroxisome proliferator-activated receptor α (PPARα) in primary endothelial cells.
Life Sci, 67 (2000), pp. 863-876
[24.]
S. Grip, S. Janciauskiene, S. Lindgren.
Atorvastatin activates PPAR-γ and attenuates the inflammatory response in human monocytes.
Inflamm Res, 51 (2002), pp. 58
[25.]
I. Inoue, F. Itoh, S. Aoyagi, S. Tazawa, H. Kusama, M. Akahane, et al.
Fibrate and statin synergistically increase the transcriptional activities of PPARα/RXRα and decrease the transactivation of NF-κB.
Biochem Biophys Res Commun, 290 (2002), pp. 131-139
[26.]
G. Martin, H. Duez, C. Blanquart, V. Berezowski, P. Poulain, J.C. Fruchart, et al.
Statin-induced inhibition of the Rho-signaling pathway activates PPARα and induces HDL apoA-I.
J Clin Invest, 107 (2001), pp. 1423-1432
[27.]
J.F. Landrier, C. Thomas, J. Grober, H. Duez, F. Percevault, M. Souidi, et al.
Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is peroxisome proliferator-activated receptorα-dependent.
J Biol Chem, 279 (2004), pp. 45512-45518
[28.]
N. Roglans, E. Sanguino, C. Peris, M. Alegret, M. Vázquez, T. Adzet, et al.
Atorvastatin treatment induced peroxisome proliferator-activated receptor α expression and decreased plasma nonesterified fatty acids and liver triglyceride in fructose-fed rats.
J Pharmacol Exp Ther, 302 (2002), pp. 1-8
[29.]
Sanguino E, Roglans N, Alegret M, Sánchez RM, Vázquez-Carrera M, Laguna JC. Atorvastatin reverses age-related reduction of rat hepatic PPARα and HNF-4. Br J Pharmacol. 2005. En prensa.
[30.]
A. Bowie, L.A.J. O’Neill.
Oxidative stress and nuclear factor-κB activation. A reassessment of the evidence in the light of recent discoveries.
Biochem Pharmacol, 59 (2000), pp. 13-23
[31.]
M. Ortego, C. Bustos, M.A. Hernández-Presa, J. Tunon, C. Díaz, G. Hernández, et al.
Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells.
Atherosclerosis, 147 (1999), pp. 253-261
[32.]
A. Cabrero, J.C. Laguna, M. Vázquez.
Peroxisome proliferator-activator receptors and the control of inflammation.
Cur Drug Targets Inflamm Allergy, 1 (2002), pp. 243-248
[33.]
P. Delerive, P. Gervois, J.C. Fruchart, B. Staels.
Induction of IkBα expression as a mechanism contributing to the antiinflammatory activities of peroxisome proliferator-activated receptor α activators.
J Biol Chem, 275 (2000), pp. 36703-36707
[34.]
P. Delerive, K. De Bosscher, S. Besnard, W. Vanden Berghe, J.M. Peters, F.J. González, et al.
Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factor NF-kappaB and AP-1.
J Biol Chem, 274 (1999), pp. 32048-32054
[35.]
A. Cabrero, M. Alegret, R.M. Sánchez, J.C. Laguna, M. Vázquez-Carrera.
Increased reactive oxygen species production down-regulates peroxisome proliferator-activated α pathway in C2C12 skeletal muscle cells.
J Biol Chem, 277 (2002), pp. 10100-10107
[36.]
A. Planavila, J.C. Laguna, M. Vázquez-Carrera.
Atorvastatin improves peroxisome proliferator-activated receptor signaling in cardiac hypertrophy by preventing nuclear factor-κB activation.
Biochim Biophys Acta, 1687 (2005), pp. 76-83
Copyright © 2005. Sociedad Española de Arteriosclerosis y Elsevier España S.L.
Opciones de artículo
Herramientas
es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos