Acção imunomodeladora dos fármacos hipolipemiantes
Palavras-chave:
Aterosclerose, doença cardiovascular, inflamação, imunidade, hipolipemiantesResumo
A doença aterosclerótica é a principal causa de morte nos países desenvolvidos e, subjacente à sua patogénese, parece estar uma reacção do vaso a uma qualquer agressão física, química, infecciosa ou imunológica. Seja qual for o factor responsável pela agressão, os mecanismos inflamatórios e imunológicos exercem um papel primordial na ampliação e manutenção do processo aterogénico. De todos os factores de risco conhecidos, o aumento do colesterol sérico, nomeadamente da sua fracção LDL, constitui um dos mais importantes, admitindo alguns autores que muitos dosoutros factores de risco só actuarão quando simultaneamente existir uma hipercolesterolemia. Assim, os fármacos hipocolesterolémicos têm um papel central na prevenção e no tratamento da doença cardiovascular, como atestam diversos ensaios de prevenção primária e secundária. Para além do seu efeito a nível dos lípidos, os diversos hipolipemiantes, particularmente as estatinas e os fibratos, apresentam diversas acções a nível dos mecanismos inflamatórios e imunes que, embora não completamente esclarecidos, se revestem do maior interesse terapêutico. O presente artigo procura fazer uma revisão sobre as acções anti-inflamatórias e imunológicas dos diferentes fármacos hipolipemiantes, particularmente das estatinas, dos fibratos e do probucol.
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Wiick G. Millonig G. Xu Q. 1-The autoimmunc pathogencsis of athcrosekrosis-an evolutionary-Darwinian eoneept. Editors; Yehuda Shocnldd, Dror Harats and Georg Wick. ln; Atherosclcrosis and Autoimmunity .. Amsterdam; Elsevier Sciem:e. 2001; 5-16
Goran K Hanson. Cell-mt'diated immunity in atherosckrosis. Currcnt Opinion in Lipidilogy 1997: 8: 301-311.
George J. Harats D. Gilhurd 13. Shoenfeld Y. Emt'rging cross rcgulatory roks of imnrnnity and autoimnrnnity in atherosclcrosis. lmmunologic Rcsan:h 19%:15(4); 315-322.
Frostegard J. Ulfgren Ak. Nyhcrg P. et al. Cytokine expression in advanced human atherosclcrotic plaque, ; dominance of pro inflamatory (Th 1) and macrophage-stimulating cytokines. Atherosclcrosis 1999: 145: 33--13.
Gcorgd ..Harats D. Gilhurd B. Levy Y. Langevitz P. Shoenfeld Y. Atherosclorosis-rclatcd markers in systemic lupus crythematosus
patients: the role of humoral immunity in enhanced atherogenesis. Lupus 1999:8 (3): 220-226.
Vaarala O. Antiphospholipid antibodies and atherosclerosis. Lupus 1996: 5(5): 442-447.
Ellis RW. lnfection and coronary heart disease. J Med Microbiol 1997: 46: 535-539.
Danesh J. Collins R. Peto R. Chronic infections and i:oronary heart disease: is there a link? Lancet 1997 :350:430-436.
Kallen J. Welzcnbai:h K. Ramage P. et al. Structural basis for LFA- 1 inhibition upon lovastatin binding to the CD 11a 1-domain. Journal of Molecular Biology 1999:292 (1): 1-9.
Vrtovsnik F. Essig M. limura O. Friedlander G. Effect of lipid lowering strategies on tubular cell biology. Kidney lnternational supplement 1999: 71: S92-96.
Sugiura T. Wada A. Moryama T. et al. Probucol supresses ICAM- 1 expression in rat mesangial cells: posible role of IL-1. Kidney lnternational-supplement 1999; 71: S 167-170.
Rosenson RS. Tangney CC. Casey LC. lnhibition of pro inflammatory cytokine by pravastatin. Lancet 1999:353 (9157): 983-984.
Kirk G. McLaren M. Muir AH. Stonebridge PA. Belch JJ. Decrease in P-selentin leveis in patients with hypercholesterolaemia and peripheral arterial occlusive disease after lipid-lowering treatment. Vascular Medicine 1999;4 ( 1 ):23-26.
lkeda U. Shimada K. Statins and monocyts. Lancet 1999: 353 (9169): 2070.
lkeda U. Shimada K. Statins and C-reactive protein. Lancet 1999:353(9160):1274-1275.
Kobashigawa JA. Katznelson S. Laks H. et al. Effect of pravastatin on outcomes after cardiac transplantation. N England J Med 1995: 333: 621-627.
Katznelson S. Wang XM. Chia D. et al. The inhibitory effects of pravastatin on natural killer cell activity in vivo and on cytotoxic: T lymphocyte activity in vitro. Journal of Heart and Lung Transplantation. 1998: 17 (4) :335-340.
Sparrow P. Burton A. Hermandez M et ai. Simvastatin has anti inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering. Arteriosclcrosis. Thrombosis and Vascular Biology 2001: 21: 115-121.
Maggard MA. KeB. Wang T. Kaldas F. et ai. Effects of pravastatin on chronic rejection of cardiac allografts. Transplantation 1998: 65: 149-155.
Kwak B. Mulhaupt F. Veillard N et al. The HMG-CoA reductase inhibitor simvastatin inhibits INF-gamma induced MHC class II expression in human vascular endothelial cells. Schwciz Med Wochenschr 2001 : 131: 41-46.
Kwak B. Mulhaupt F. Myit S. et al. Statins as a newly recognized of immunomodulator. Nat Med 2000: 6: 1399-1402.
Ridker PM. Rifai N. Pfdfrr MA el al. Long term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999: 100:230-235.
Ferro D. Parrotto S. Basili S. Alessandri C. Viloi F. Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hyperchoksterolemia. Journal of American College of Cardiology 2000: 36: 427-431.
Weber C. Erl W. Weber KS et al. HMG-CoA reductase inhibitors decrease CD 1 1 b expression and CD 1 1 b-dependentnadhesion of monocyts to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. Journal of the American College of Cardiology 1997:30(5): 1212-1217.
Sardo MA. Castaldo M. Cinquegrani M et al. Effects of simvastatin tratment on slCAM-1 and sE-selectin leveis in hyper-cholesternlemic subjects. Atherosclerosis. 2001: 155: 143-147.
Murphy RT. Foley JB. Mulvihill N ct al. lmpact of preexisting statin use on adhesion molecule expression in patients presenting with acute coronary syndromes. Amcrican journal of cardiology 2001: 87: 446-448.
Ncgre Aminou P. van Erck M, van Leeuwen RE et al Differential effect of simvastatin on various signal transduction intermediates in cultured human smooth muscle cells. Biochem Pharmacol 2001; 61: 991-998.
Knapp AC. Huang J, Starling G, Kiener PA. lnhibitors of HMG CoA reductase sensitize human smooth muscle cells 10 Fas-ligand and cytokine-induced cell death. Atherosclerosis 2000: 152: 217-227.
Park YS. Guijarro C. Kim Y et al. Lovastatin reduces glomerular macrophage inllux and expression of monocyte chemoallractant protein-1 mRNA in nephrotic rats. American Journal of Kidney Diseases 1998: 31( 1) : 190-194.
Kim SI. Han DC, Lee HB. Lovastatin inhibits transforming growth factor-beta I expression in diabetic rat glomeruli and cultured rat mesangial cells. Journal of the American Society of Nephrology 2000;11: 80-87.
Romano M. Diomede L. Sironi M et al. Inhibition of monocyte chemotactic protein by statins.Laboratory Investigation 2000; 80: 1095-1100.
Massy ZA. Kim Y. Guijarro C el al. Low-density lipoprotein induced expression of interleukin-6, a marker of human mesangial cell inllammation: effecls of oxidation and modulation by lovastatin. Biochemical and Biophysical Research Communications. 2000; 267: 536-540.
Felezko W. Balkowiec EZ. Sieberth et al. Lovastatin and tumor necrosis factor-alpha exhibit potentiated antitumor effects against Ha-ras-transformed murine tumor via inhibition of tumor-induced angiogenesis. International Journal of Cancer 1999; 81(4):560-567.
McCarty. Supression of dolichol synthesis with isoprenoids and statins may potentiate the cancer-retardant efficacy of IGF-1 down-regulalion. Med Hypotheses 2001; 56: 12-16.
Pahan K. Sheikh FG. Namboodiri AM et al. Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia. and macro phagcs.Journal of Clinical lnvestigation 1997:100( 11):2671-2679.
Sadeghi MM. Collinge M. Pardi R. Bender JR. Simvastatin modulates cytokine-mediated endothelial cell adhesion molecule induction: involvement of an inhibitory G protein. Journal Immunology 2000: 165: 2712-2718.
Ruotolo G. Ericsson C. Te1tamanti C. ct al. Treatment effects on serum lipoproteins lipids. apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables 10 progression of coronary artery disease in the bezafibrate coronary atherosclerosis intervention triai (BECAITJ. Journal of the American College of Cardiology 1998: 32: 1648-1656.
Frick M. Syvanne M. Nieminen M et al. Prevention of the angiographic progression of coronary and vein graft mherosclerosis, by gemfibrozil afler coronary surgery in men with low levels of HDL cholesterol. Circulation 1997; 96: 2137-2143.
Mmlej A. Okopien B. Kowalski J et al. Effects of fenofibrat on plasma cytokine concentrations in patients with atherosclcrosis and hyperlipoprotcinemia II b. lnternational Journal of Clinical Pharmacology and Therapeutics 1998;36(6): 345-349.
Chinelli G. Griglio S. Antonucci M et al. Activation of Proliferator activated Receptors alpha and Beta lnduces Apoptosis of Human Monocyte-derived Macrophages. The Journal of Biological Chemistry 1998 ; 273:25573-25580.
Devchand P. Keller H. Peters J. et ai. The PPAR alpha-leukotriene 84 pathway to inflammation control. Nature 1996 ;384: 39-43.
Delerive P. Bosseher K. Besnard S. et al. Peroxisome proliferator receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-lalk with transcription factors NF-KB and AP-1. The Journal of Biological Chemistry 1999 ; 274: 32048-32054.
Marx N. Sukhova G. Collins T et al. PPAR alpha activators inhibit cytokine-induced vascular cell adhesion rnolecule-1 expression in human cndothclial cells. Circulation 1999; 99: 3125-3131
Staels B, Koenig W, Habib A. et al. Activation of human aortic smooth-muscle cells is inhibited by PPAR alpha but not by PPAR gama activators. Nature 1998 : 393: 790-793.
Sugiura T. Wada E. Yamauchi A. Horio M. Imai E. Hori M.Probucol inhibits intercellular adhesion molecule-1 expression on cultured rat mesangial cells. Nephrolo. 1998: 4: 75-80
Zapolska-Downar D, Zapolski-Downar A. Markiewski M et al. Selective inhibition by probucol of vascular cell adhesion molceule-
(VCAM-1) expression in human vascular endothelial cells. Atherosclerosis 2001: 155: 123-130.
Li LX. Chen JX. Liao DF. Yu L. Probucol inhibits oxidized-low density lipoprotein-induced adhesion of monocytes to endothelial cells by reducing P-selectin synthesis in vitro. Endothclium 1998: 6: 1-8.
Fruebis J, Gonzalez V. Silvestre M. et al. Effect of probucol treatment on gene expresión of YCAM-1. MCP-1. and M-CSF in the aortic wall of LDL receptor-deficient rabbits during early atherogenesis. Arteriosclerosis. Thrombosis and Vascular Biology 1997; 17(7): 1289-1302.
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