Información del artículo
Resumen
En la formación de nuevos vasos intervienen las células endoteliales progenitoras circulantes (vasculogénesis) y las células endoteliales vasculares (angiogénesis). Recientemente se ha demostrado que los inhibidores de la HMG-CoA reductasa (estatinas) a dosis hipolipemiantes potencian la vasculogénesis y que, en general, a dosis bajas potencian la angiogénesis; sin embargo a dosis altas la inhiben. El mecanismo a través del cual ejercen estos efectos es independiente de su efecto hipolipemiante. En la actualidad se desconoce si parte de su efecto cardioprotector puede deberse a éstos u otros efectos pleiotrópicos. La mayoría de los estudios clínicos indican que las estatinas no incrementan la incidencia de cáncer; por el contrario, según datos del estudio 4S, estos fármacos podrían reducir la incidencia de cáncer. Sin embargo, se necesitan estudios clínicos diseñados específicamente para determinar si las estatinas pueden modular la angiogénesis y, de ese modo, afectar al crecimiento y a la propagación de tumores.
Palabras clave:
Angiogénesis
Células endoteliales progenitoras
Estatinas
Cáncer
Abstract
Circulating endothelial progenitor cells (vasculogenesis) and vascular endothelial cells (angiogenesis) play a role in the formation of new vessels. Recently, HMG-CoA reductase inhibitors (statins) at lipid lowering doses have been demonstrated to promote vasculogenesis and, at low doses, to promote angiogenesis; high doses, however, inhibit angiogenesis. The mechanism through which they exert these effects is independent of their lipid lowering effect. Currently, it is not known whether their cardioprotective effect could be due to these effects or to other pleiotropic effects. Most clinical studies indicate that statins do not increase the incidence of cancer; on the contrary, according to data from the 4S study, these drugs could reduce it. However, clinical studies specifically designed to determine whether statins can modulate angiogenesis and thus affect the growth and propagation of tumors are required.
Key words:
Endothelial progenitor cells
Statins
Cancer
El Texto completo está disponible en PDF
Bibliografía
[1.]
T. Asahara, T. Murohara, A. Sullivan, M. Silver, R. Van der Zee, T. Li, et al.
Isolation of putative progenitor endothelial cells for angiogenesis.
Science, 275 (1997), pp. 964-967
[2.]
T. Asahara, H. Masuda, T. Takahashi, C. Kalka, C. Pastore, M. Silver, et al.
Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization.
Circ Res, 85 (1999), pp. 221-228
[3.]
T. Takahashi, C. Kalka, H. Masuda, D. Chen, M. Silver, M. Kearney, et al.
Ischemia-and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization.
Nat Med, 5 (1999), pp. 434-438
[4.]
C. Kalka, H. Masuda, T. Takahashi, W.M. Kalka-Moll, M. Silver, M. Kearney, et al.
Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization.
Proc Natl Acad Sci USA, 97 (2000), pp. 3422-3427
[5.]
J. Llevadot, S. Murasawa, Y. Kureishi, S. Uchida, H. Masuda, A. Kawamoto, et al.
HMG-CoA reductase inhibitor mobilizes bone marrow: derived endothelial progenitor cells.
J Clin Invest, 108 (2001), pp. 399-405
[6.]
S. Dimmeler, A. Aicher, M. Vasa, C. Mildner-Rihm, K. Adler, M. Tiemann, et al.
HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway.
J Clin Invest, 108 (2001), pp. 391-397
[7.]
M. Vasa, S. Fichtlscherer, K. Adler, A. Aicher, H. Martin, A.M. Zeiher, et al.
Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease.
Circulation, 103 (2001), pp. 2885-2890
[8.]
B. Assmus, C. Urbich, A. Aicher, W.K. Hofmann, J. Haendeler, L. Rossig, et al.
HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes.
Circ Res, 92 (2003), pp. 1049-1055
[9.]
Y. Hidaka, T. Eda, M. Yonemoto, T. Kamei.
Inhibition of cultured vascular smooth muscle cell migration by simvastatin (MK-733).
Atherosclerosis, 95 (1992), pp. 87-94
[10.]
J. Martínez-González, L. Badimon.
Human and porcine smooth muscle cells share similar proliferation dependence on the mevalonate pathway: implication for in vivo interventions in the porcine model.
Eur J Clin Invest, 26 (1996), pp. 1023-1032
[11.]
L. Vincent, W. Chen, L. Hong, F. Mirshahi, Z. Mishal, T. Mirshahi-Khorassani, et al.
Inhibition of endothelial cell migration by cerivastatin, an HMG-CoA reductase inhibitor: contribution to its antiangiogenic effect.
FEBS Lett, 495 (2001), pp. 159-166
[12.]
Y. Kureishi, Z. Luo, I. Shiojima, A. Bialik, D. Fulton, D.J. Lefer, et al.
The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals.
Nat Med, 6 (2000), pp. 1004-1010
[13.]
H.J. Park, D. Kong, L. Iruela-Arispe, U. Begley, D. Tang, J.B. Galper.
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors interfere with angiogenesis by inhibiting the geranylgeranylation of RhoA.
Circ Res, 91 (2002), pp. 143-150
[14.]
L. Vincent, C. Soria, F. Mirshahi, P. Opolon, Z. Mishal, J.P. Vannier, et al.
Cerivastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase, inhibits endothelial cell proliferation induced by angiogenic factors in vitro and angiogenesis in vivo models.
Arterioscler Thromb Vasc Biol, 22 (2002), pp. 623-629
[15.]
M. Weis, C. Heeschen, A.J. Glassford, J.P. Cooke.
Statins have biphasic effects on angiogenesis.
Circulation, 105 (2002), pp. 739-745
[16.]
C. Urbich, E. Dernbach, A.M. Zeiher, S. Dimmeler.
Double-edged role of statins in angiogenesis signaling.
Circ Res, 90 (2002), pp. 737-744
[17.]
A. Brouet, P. Sonveaux, C. Dessy, S. Moniotte, J.L. Balligand, O. Feron.
Hsp90 and caveolin are key targets for the proangiogenic nitric oxide-mediated effects of statins.
Circ Res, 89 (2001), pp. 866-873
[18.]
T. Shimada, Y. Takeshita, T. Murohara, K. Sasaki, K. Egami, S. Shintani, et al.
Angiogenesis and vasculogenesis are impaired in the precocious-aging klotho mouse.
Circulation, 110 (2004), pp. 1148-1155
[19.]
T. Okamoto, S. Yamagishi, Y. Inagaki, S. Amano, K. Koga, R. Abe, et al.
Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin.
FASEB J, 16 (2002), pp. 1928-1930
[20.]
U. Laufs, J.K. Liao.
Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase.
J Biol Chem, 273 (1998), pp. 24266-24271
[21.]
J. Martínez-González, B. Raposo, C. Rodríguez, L. Badimon.
3-hydroxy- 3-methylglutaryl coenzyme a reductase inhibition prevents endothelial NO synthase down regulation by atherogenic levels of native LDLs: balance between transcriptional and postranscriptional regulation.
Arterioscler Thromb Vasc Biol, 21 (2001), pp. 804-809
[22.]
J. Chen, Z.G. Zhang, Y. Li, Y. Wang, L. Wang, H. Jiang, et al.
Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke.
Ann Neurol, 53 (2003), pp. 743-751
[23.]
D. Fulton, J.P. Gratton, T.J. McCabe, J. Fontana, Y. Fujio, K. Walsh, et al.
Regulation of endothelium-derived nitric oxide production by the protein kinase Akt.
Nature, 399 (1999), pp. 597-601
[fe de errores en: Nature 1999;400:792]
[24.]
S. Dimmeler, I. Fleming, B. Fisslthaler, C. Hermann, R. Busse, A.M. Zeiher.
Activation of nitric oxide synthase in endothelial cells by Aktdependent phosphorylation.
Nature, 399 (1999), pp. 601-605
[25.]
S. Rupp, C. Badorff, M. Koyanagi, C. Urbich, S. Fichtlscherer, A. Aicher, et al.
Statin therapy in patients with coronary artery disease improves the impaired endothelial progenitor cell differentiation into cardiomyogenic cells.
Basic Res Cardiol, 99 (2004), pp. 61-68
[26.]
I. Pourati, C. Kimmelstiel, W. Rand, R.H. Karas.
Statin use is associated with enhanced collateralization of severely diseased coronary arteries.
Am Heart J, 146 (2003), pp. 876-881
[27.]
B. Assmus, V. Schächinger, C. Teupe, M. Britten, R. Lehmann, N. Dobert, et al.
Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCAREAMI).
Circulation, 106 (2002), pp. 3009-3017
[28.]
V. Schächinger, B. Assmus, M.B. Britten, J. Honold, R. Lehmann, C. Teupe, et al.
Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial.
J Am Coll Cardiol, 44 (2004), pp. 1690-1699
[29.]
J.L. Bos.
Ras oncogenes in human cancer: a review.
Cancer Res, 49 (1989), pp. 4682-4689
[fe de errores: Cancer Res 1990;50:1352]
[30.]
R.J. Doll, P. Kirschmeier, W.R. Bishop.
Farnesyltransferase inhibitors as anticancer agents: critical crossroads.
Curr Opin Drug Discov Devel, 7 (2004), pp. 478-486
[32.]
M.R. Graaf, D.J. Richel, C.J.F. 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
[33.]
W. Feleszko, E.Z. Balkowiec, E. Sieberth, M. Marczak, A. Dabrowska, A. Giermasz, et al.
Lovastatin and tumor necrosis factor-alpha exhibit potentiated antitumor effects against Ha-ras-transformed murine tumor via inhibition of tumor-induced angiogenesis.
Int J Cancer, 81 (1999), pp. 560-567
[34.]
A. Horiguchi, M. Sumitomo, J. Asakuma, T. Asano, T. Asano, M. Hayakawa.
3-hydroxy-3-methylglutaryl-coenzyme. A reductase inhibitor, fluvastatin, as a novel agent for prophylaxis of renal cancer metastasis.
Clin Cancer Res, 10 (2004), pp. 8648-8655
[35.]
M. Sata, H. Nishimatsu, J. Osuga, K. Tanaka, N. Ishizaka, S. Ishibashi, et al.
Statins augment collateral growth in response to ischemia but they do not promote cancer and atherosclerosis.
Hypertension, 43 (2004), pp. 1214-1220
[36.]
Z. Ungvari, P. Pacher, A. Csiszar.
Can simvastatin promote tumor growth by inducing angiogenesis similar to VEGF?.
Med Hypotheses, 58 (2002), pp. 85-86
[37.]
D. Jacobs, H. Blackburn, M. Higgins, D. Reed, H. Iso, G. McMillan, et al.
Report of the conference on low blood cholesterol: mortality associations.
Circulation, 86 (1992), pp. 1046-1060
[38.]
G. Davey Smith, J. Pekkanen.
Should there be a moratorium on the use of cholesterol lowering drugs?.
BMJ, 304 (1992), pp. 431-434
[39.]
T.B. Newman, S.B. Hulley.
Carcinogenicity of lipid-lowering drugs.
JAMA, 275 (1996), pp. 55-60
[40.]
F.M. Sacks, M.A. Pfeffer, L.A. Moye, J.L. Rouleau, J.D. Rutherford, T.G. Cole, 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, 335 (1996), pp. 1001-1009
[41.]
J. Shepherd, G.J. Blauw, M.B. Murphy, E.L. Bollen, B.M. Buckley, S.M. Cobbe, et al.
PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
Lancet, 360 (2002), pp. 1623-1630
[42.]
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, 360 (2002), pp. 7-22
[43.]
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
[44.]
T.E. Strandberg, K. Pyorala, T.J. Cook, L. Wilhelmsen, O. Faergeman, G. Thorgeirsson, et al.
Mortality and incidence of cancer during 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S).
Lancet, 364 (2004), pp. 771-777
[45.]
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
Copyright © 2005. Sociedad Española de Arteriosclerosis y Elsevier España S.L.