Resumen
La aterosclerosis es un proceso inmunológico inflamatorio crónico que lesiona las paredes vasculares arteriales, en el que las células involucradas desempeñan un papel fundamental para la expresión de los principales mediadores (citocinas) de la acción proaterógenica y de la inducción de mecanismos anti-aterogénicos de control. En este fenómeno el inbalance entre las citocinas proinflamatorias y antinflamatorias es el principal determinante de la formación y fenotipo de la placa.
Las citocinas involucradas en la formación ó modulación de la placa aterosclerótica, actúan por medio de vías de señalización, activando mecanismos de transcripción en el núcleo, con la consecuente expresión de receptores, activación celular e inducción de mecanismos perpetuadores de control inflamatorio.
Existen factores desencadenantes primarios, que inician la cascada inflamatoria, como la presencia de niveles ele- vados de LDL oxidada el factor que más temprano inicia la actividad aterogénica. De igual manera; otros factores desencadenantes secundarios, participan en el mantenimiento y amplificación de la producción de citocinas en las lesiones ateroscleróticas, incluyendo la presencia de factores mecánicos, niveles de angiotensina II, radicales libres, metaloproteinasas, agentes infecciosos entre otros.
La investigación básica ha ayudado a explicar los mecanismos de acción de algunos de los fármacos usados para combatir la enfermedad, sin embargo existen varios aspectos de la formación y evolución de la placa que permanecen sin aclarar, entre otros por que la mayoría de los mecanismos de aterogénesis están basados en modelos animales.
Citas
Tedgui A, Mallat Z. Cytokines in atherosclerosis: Pathogenic and regulatory pathways. Physiol Rev 2006, 86; 515-581.
Janssen-Heininger YM, Poynter ME, and Baeuerle PA. Recent advances towards understanding redox mechanisms in the activation of nuclear factor _B. Free Radic Biol Med. 2000, 28: 1317–1327.
Lawrence T, Gilroy DW, Colville-Nash PR, and Willoughby DA. Possible new role for NF-kappaB in the resolution of inflammation. Nat Med 2001, 7: 1291–1297.
Dong C, Yang DD, Tournier C, et al. JNK is required for effector T-cell function but not for T-cell activa- tion. Nature 2000, 405: 91–94.
Sabapathy K, Hu Y, Kallunki T, et al. JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development. Curr Biol 1999, 9: 116–125.
Kwak B, Mulhaupt F, Myit S, and Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000, 6: 1399–1402.
Leung BP, Sattar N, Crilly A, et al. A novel anti- inflammatory role for simvastatin in inflammatory arthritis. J Immunol 2003, 170: 1524–1530.
Nath N, Giri S, Prasad R, et al. Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy. J Immunol 2004, 172: 1273–1286.
Youssef S, Stuve O, Patarroyo JC, et al. The HMG- CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 2002, 420: 78–84.
Grainger DJ. Transforming growth factor beta and atherosclerosis: so far, so good for the protective cytokine hypothesis. ArteriosclerThromb Vasc Biol 2004, 24: 399–404.
Mallat Z and Tedgui A. Immunomodulation to combat atherosclerosis:the potential role of immune regulatory cells. Exp OpinBiol Ther 2004, 4: 1387– 1393.
Mallat Z and Tedgui A. The role of transforming growth factor beta in atherosclerosis: novel insights and future perspectives. Curr Opin Lipidol 2002, 13: 523–529.
Bjorkbacka H, Kunjathoor VV, Moore KJ, et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med 2004, 10: 416–421.
Ait Oufella H, Salomon BL, Potteaux S, et al. Natu- ral regulatory T cells control the development of ath- erosclerosis in mice. Nat Med. 2006, 12 (2): 178-80.
Quinn MT, Parthasarathy S, Fong LG, and Stein- berg D. Oxidatively modified low density lipopro- teins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci USA 1987, 84: 2995–2998.
Brown MS and Goldstein JL. Lipoprotein metabo- lism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem 1983, 52: 223–261.
Witztum JL and Steinberg D. The oxidative modifi- cation hypothesis of atherosclerosis: does it hold for humans? Trends Cardiovasc Med 2001, 11: 93–102.
Aikawa M, Rabkin E, Okada Y, et al. Lipid lower- ing by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization. Circula- tion 1998, 97: 2433–2444.
Kockx MM, De Meyer GR, Buyssens N, et al. Cell composition, replication, and apoptosis in athero- sclerotic plaques after 6 months of cholesterol with- drawal. Circ Res 1998, 83: 378–387.
Corti R, Fuster V, Fayad ZA, et al. Effects of aggressive versus conventional lipid-lowering therapy by simvastatin on human atherosclerotic lesions: a prospective, randomized, double-blind trial with high-resolution magnetic resonance imaging. J Am Coll Cardiol 2005, 46: 106–112.
Corti R, Fuster V, Fayad ZA, et al. Lipid lowering by simvastatin induces regression of human atheroscle- rotic lesions: two years’ follow-up by high-resolution noninvasive magnetic resonance imaging. Circulation 2002, 106: 2884–2887.
Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclero- sis: a randomized controlled trial. JAMA 2004, 291: 1071–1080.
Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005, 352: 29–38.
Navab M, Ananthramaiah GM, Reddy ST, et al. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J Lipid Res 2004, 45: 993–1007.
Helgadottir A, Manolescu A, Thorleifsson G, et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 36: 233–239, 2004.
Caro CG, Fitz-Gerald JM, and Schroter RC. Ath- eroma and arterial wall shear. Proc R Soc Lond B Biol Sci 1971, 117: 109–159.
Cunningham KS and Gotlieb AI. The role of shear stress in the pathogenesis of atherosclerosis. Lab Invest 2005, 85: 9–23.
Davies PF. Flow-mediated endothelial mechano- transduction. Physiol Rev 1995, 75: 519–560.
Hajra L, Evans AI, Chen M, et al. The NF-_B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to ath- erosclerotic lesion formation. Proc Natl Acad Sci USA 2000, 97: 9052–9057.
Mazzolai L, Duchosal M, Korber M, et al. Endog- enous angiotensin II induces atherosclerotic plaque vulnerability and elicits a Th1 response in apoE_/_ mice. Hypertension 2004, 44: 277–282.
Hayakawa M, Miyashita H, Sakamoto I, et al. Evi- dence that reactive oxygen species do not mediate NF-kappaB activation. EMBO J 2003, 22: 3356– 3366.
Nishi T, Shimizu N, Hiramoto M, et al. Spatial redox regulation of a critical cysteine residue of NF- kappa B in vivo. J Biol Chem 2002, 277: 44548–44556.
Rossi A, Kapahi P, Natoli G, et al. Anti-inflamma- tory cyclopentenone prostaglandins are direct inhibi- tors of IkappaB kinase. Nature 2000, 403: 103–108.
Proudfoot JM, Croft KD, Puddey IB, and Beilin LJ. Angiotensin II type 1 receptor antagonists inhibit basal as well as lowdensity lipoprotein and platelet- activating factor-stimulated human monocyte che- moattractant protein-1. J Pharmacol Exp Ther 2003, 305:846–853.
Dinarello CA, Ikejima T, Warner SJ, et al. Interleu- kin 1 induces interleukin 1. I. Induction of circulating interleukin 1 in rabbits in vivo and in human mono- nuclear cells in vitro. J Immunol 1987, 139: 1902–1910.
Cavaillon JM, Adib-Conquy M, Fitting C, et al. Cytokine cascade in sepsis. Scand J Infect Dis 2003, 35: 535–544.
Lord GM, Matarese G, Howard JK, et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998, 394: 897– 901.
Matarese G, Carrieri PB, La Cava A, et al. Leptin increase in multiple sclerosis associates with reduced number of CD4 + CD25 + regulatory T cells. Proc Natl Acad Sci USA 2005, 102: 5150–5155.
Bokarewa M, Nagaev I, Dahlberg L, et al. Resistin, an adipokine with potent proinflammatory proper- ties. J Immunol 2005, 174: 5789–5795.
Kumada M, Kihara S, Ouchi N, et al. Adiponectin specifically increased tissue inhibitor of metallopro- teinase-1 through interleukin-10 expression in human macrophages. Circulation 2004, 109: 2046–2049.
Pockley AG, Georgiades A, Thulin T, et al. Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hyper- tension. Hypertension 2003, 42: 235–238.
Binder CJ, Chang MK, Shaw PX, et al. Innate and acquired immunity in atherogenesis. Nat Med 2002, 8: 1218–1226.
Basta G, Lazzerini G, Del Turco S, et al. At least 2 distinct pathways generating reactive oxygen spe- cies mediate vascular cell adhesion molecule-1 induc- tion by advanced glycation end products. Arterioscler Thromb Vasc Biol 2005, 25: 1401–1407.
Basta G, Lazzerini G, Massaro M, et al. Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses. Circula- tion 2002, 105: 816–822.
Hugel B, Martinez MC, Kunzelmann C, and Freys- sinet JM. Membrane microparticles: two sides of the coin. Physiology 2005, 20:22–27.
O’Connor CM, Dunne MW, Pfeffer MA, et al. Azithromycin for the secondary prevention of coro- nary heart disease events: the WIZARD study: a ran- domized controlled trial. JAMA 2003, 290: 1459–1466.
Zahn R, Schneider S, Frilling B, et al. Antibiotic therapy after acute myocardial infarction: a prospective randomized study. Circulation 2003, 107: 1253-1259.
Grayston JT, Kronmal RA, Jackson LA, et al. Azithromycin for the secondary prevention of coro- nary events. N Engl J Med 2005, 352: 1637–1645.
Cercek B, Shah PK, Noc M, et al. Effect of short- term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syn- drome in the Azithromycin in Acute Coronary Syn- drome (AZACS) trial: a randomised controlled trial. Lancet 2003, 361:809–813.
Cannon CP, Braunwald E, McCabe CH, et al. Antibiotic treatment of Chlamydia pneumoniae after
acute coronary syndrome. N Engl J Med 2005, 352: 1646–1654.
Grandaliano G, Valente AJ, and Abboud HE. A novel biologic activity of thrombin: stimulation of monocyte chemotactic protein production. J Exp Med 1994, 179: 1737–1741.
Kaplanski G, Fabrigoule M, Boulay V, et al. Thrombin induces endothelial type II activation in vitro: IL-1 and TNF-alpha-independent IL-8 secretion and E-selectin expression. J Immunol 1997, 158: 5435–5441.
Durk T, Panther E, Muller T, et al. 5-Hydroxy- tryptamine modulates cytokine and chemokine production in LPS-primed human monocytes via stimulation of different 5-HTR subtypes. Int Immunol 2005, 17: 599–606.
Olsen NJ and Stein CM. New drugs for rheu- matoid arthritis. N Engl J Med 2004, 350: 2167– 2179.
Randle JC, Harding MW, Ku G, et al. ICE/ caspase-1 inhibitors as novel anti-inflammatory drugs. Exp Opin Invest Drugs 2001, 10: 1207–1209.
Borie DC, Changelian PS, Larson MJ, et al. Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly pro- longs kidney allograft survival in nonhuman pri- mates. Transplantation 2005, 79: 791–801.
Shouda T, Yoshida T, Hanada T, et al. Induc- tion of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest 2001, 108: 1781–1788.
Mallat Z, Gojova A, Brun V, et al. Induction of a regulatory T cell type 1 response reduces the development of atherosclerosis in apolipo- protein E-knockout mice. Circulation 2003, 108: 1232–1237.
Briner TJ, Kuo MC, Keating KM, et al. Periph- eral T-cell tolerance induced in naive and primed mice by subcutaneous injection of peptides from the major cat allergen Feld I. Proc Natl Acad Sci USA 1993, 90: 7608–7612.
Gerrity RG. The role of the monocyte in athero- genesis. II. Migration of foam cells from athero- sclerotic lesions. Am J Pathol 1981, 103:191–200.
Llodra J, Angeli V, Liu J, Trogan E, et al. Emi- gration of monocyte-derived cells from athero- sclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci USA 2004, 101: 11779–11784.
Esta obra está bajo una licencia internacional Creative Commons Atribución-NoComercial-SinDerivadas 4.0.