Parasitology Research

, Volume 112, Issue 7, pp 2731–2739

Protection of vascular endothelium by aspirin in a murine model of chronic Chagas’ disease

  • Alfredo Molina-Berríos
  • Carolina Campos-Estrada
  • Michel Lapier
  • Juan Duaso
  • Ulrike Kemmerling
  • Norbel Galanti
  • Jorge Ferreira
  • Antonio Morello
  • Rodrigo López-Muñoz
  • Juan Diego Maya
Original Paper

Abstract

Chronic Chagas’ disease affects 10–30 % of patients infected with Trypanosoma cruzi, and it mainly manifests as cardiomyopathy. Important pathophysiological mechanisms involved in the cardiac lesions include activation of the endothelium and induced microvascular alterations. These processes involve the production of endothelial adhesion molecules and thromboxane A2, which are involved in inflammatory cell recruitment and platelet aggregation, respectively. Cyclooxygenase inhibitors such as aspirin decrease thromboxane production and alter the course of Chagas’ disease, both in the acute and chronic phases. We studied the effects of the administration of low and high doses of aspirin during the early phase of T. cruzi infection, following microvascular damage in the context of a chronic murine model of Chagas’ disease. The effects of both schedules were assessed at 24 and 90 days postinfection by evaluating parasitemia, mortality, and cardiac histopathological changes as well as the expression of ICAM, VCAM, and E-selectin in cardiac tissue. Thromboxane A2, soluble ICAM, and E-selectin blood levels were also measured. While aspirin did not affect parasitemia or mortality in the infected mice, it decreased both cardiac inflammatory infiltrates and thromboxane levels. Additionally, at 90 days postinfection, aspirin normalized sICAM and sE-selectin levels. Considering the improved endothelial function induced by aspirin, we propose the possibility of including this drug in clinical therapy to treat chronic Chagas’ disease.

References

  1. Abdalla GK, Faria GE, Silva KT, Castro EC, Reis MA, Michelin MA (2008) Trypanosoma cruzi: the role of PGE2 in immune response during the acute phase of experimental infection. Exp Parasitol 118(4):514–521. doi:10.1016/j.exppara.2007.11.003 PubMedCrossRefGoogle Scholar
  2. Al-Mutairi M, Al-Harthi S, Cadalbert L, Plevin R (2010) Over-expression of mitogen-activated protein kinase phosphatase-2 enhances adhesion molecule expression and protects against apoptosis in human endothelial cells. Br J Pharmacol 161(4):782–798. doi:10.1111/j.1476-5381.2010.00952.x PubMedCrossRefGoogle Scholar
  3. Andrade D, Serra R, Svensjo E, Lima AP, Ramos ES Jr, Fortes FS, Morandini AC, Morandi V, Soeiro Mde N, Tanowitz HB, Scharfstein J (2012) Trypanosoma cruzi invades host cells through the activation of endothelin and bradykinin receptors: a converging pathway leading to chagasic vasculopathy. Br J Pharmacol 165(5):1333–1347. doi:10.1111/j.1476-5381.2011.01609.x PubMedCrossRefGoogle Scholar
  4. Ashton AW, Mukherjee S, Nagajyothi FN, Huang H, Braunstein VL, Desruisseaux MS, Factor SM, Lopez L, Berman JW, Wittner M, Scherer PE, Capra V, Coffman TM, Serhan CN, Gotlinger K, Wu KK, Weiss LM, Tanowitz HB (2007) Thromboxane A2 is a key regulator of pathogenesis during Trypanosoma cruzi infection. J Exp Med 204(4):929–940PubMedCrossRefGoogle Scholar
  5. Barbosa AP, Cardinalli Neto A, Otaviano AP, Rocha BF, Bestetti RB (2011) Comparison of outcome between Chagas’ cardiomyopathy and idiopathic dilated cardiomyopathy. Arq. Comparison of outcome between Chagas’ cardiomyopathy and idiopathic dilated cardiomyopathy Arq Bras Cardiol 97(6):517–525CrossRefGoogle Scholar
  6. Bjerre M, Kistorp C, Hansen TK, Faber J, Lip GYH, Hildebrandt P, Flyvbjerg A (2010) Complement activation, endothelial dysfunction, insulin resistance, and chronic heart failure. Scand Cardiovasc J 44(5):260–266. doi:10.3109/14017431.2010.484506 PubMedCrossRefGoogle Scholar
  7. Bryan MA, Guyach SE, Norris KA (2010) Specific humoral immunity versus polyclonal B cell activation in Trypanosoma cruzi infection of susceptible and resistant mice. PLoS Negl Trop Dis 4(7):e733. doi:10.1371/journal.pntd.0000733 PubMedCrossRefGoogle Scholar
  8. Bulckaen H, Prevost G, Boulanger E, Robitaille G, Roquet V, Gaxatte C, Garcon G, Corman B, Gosset P, Shirali P, Creusy C, Puisieux F (2008) Low-dose aspirin prevents age-related endothelial dysfunction in a mouse model of physiological aging. Am J Physiol Heart Circ Physiol 294(4):H1562–H1570. doi:10.1152/ajpheart.00241.2007 PubMedCrossRefGoogle Scholar
  9. Burger D, Touyz RM (2012) Cellular biomarkers of endothelial health: microparticles, endothelial progenitor cells, and circulating endothelial cells. J Am Soc Hypertens 6(2):85–99. doi:10.1016/j.jash.2011.11.003 PubMedCrossRefGoogle Scholar
  10. Bustamante JM, Presti MS, Rivarola HW, Fernandez AR, Enders JE, Fretes RE, Paglini-Oliva P (2007) Treatment with benznidazole or thioridazine in the chronic phase of experimental Chagas’ disease improves cardiopathy. Int J Antimicrob Agents 29(6):733–737. doi:10.1016/j.ijantimicag.2007.01.014 PubMedCrossRefGoogle Scholar
  11. Constans J, Conri C (2006) Circulating markers of endothelial function in cardiovascular disease. Clin Chim Acta 368(1–2):33–47. doi:10.1016/j.cca.2005.12.030 PubMedCrossRefGoogle Scholar
  12. Cyrus T, Sung S, Zhao L, Funk CD, Tang S, Pratico D (2002) Effect of low-dose aspirin on vascular inflammation, plaque stability, and atherogenesis in low-density lipoprotein receptor-deficient mice. Circulation 106(10):1282–1287PubMedCrossRefGoogle Scholar
  13. Danese S, Dejana E, Fiocchi C (2007) Immune regulation by microvascular endothelial cells: directing innate and adaptive immunity, coagulation, and inflammation. J Immunol J Immunol 178(10):6017–6022Google Scholar
  14. Duaso J, Rojo G, Cabrera G, Galanti N, Bosco C, Maya JD, Morello A, Kemmerling U (2010) Trypanosoma cruzi induces tissue disorganization and destruction of chorionic villi in an ex vivo infection model of human placenta. Placenta 31(8):705–711. doi:10.1016/j.placenta.2010.05.007 PubMedCrossRefGoogle Scholar
  15. Factor SM, Cho S, Wittner M, Tanowitz H (1985) Abnormalities of the coronary microcirculation in acute murine Chagas’ disease. AmJTrop Med Hyg 34(2):246–253Google Scholar
  16. Faundez M, Lopez-Munoz R, Torres G, Morello A, Ferreira J, Kemmerling U, Orellana M, Maya JD (2008) Buthionine sulfoximine has anti-Trypanosoma cruzi activity in a murine model of acute Chagas’ disease and enhances the efficacy of nifurtimox. Antimicrob Agents Chemother 52(5):1837–1839. doi:10.1128/AAC.01454-07 PubMedCrossRefGoogle Scholar
  17. Garcia S, Ramos CO, Senra JF, Vilas-Boas F, Rodrigues MM, Campos-de-Carvalho AC, Ribeiro-Dos-Santos R, Soares MB (2005) Treatment with benznidazole during the chronic phase of experimental Chagas’ disease decreases cardiac alterations. Antimicrob Agents Chemother 49(4):1521–1528. doi:10.1128/AAC.49.4.1521-1528.2005 PubMedCrossRefGoogle Scholar
  18. Herrera RN, Diaz de Amaya EI, Perez Aguilar RC, Joo Turoni C, Maranon R, Berman SG, Luciardi HL, Coviello A, Peral de Bruno M (2011) Inflammatory and prothrombotic activation with conserved endothelial function in patients with chronic, asymptomatic Chagas’ disease. Clin Appl Thromb Hemost 17(5):502–507. doi:10.1177/1076029610375814 PubMedCrossRefGoogle Scholar
  19. Hideko Tatakihara VL, Cecchini R, Borges CL, Malvezi AD, Graca-de Souza VK, Yamada-Ogatta SF, Rizzo LV, Pinge-Filho P (2008) Effects of cyclooxygenase inhibitors on parasite burden, anemia, and oxidative stress in murine Trypanosoma cruzi infection. FEMS Immunol Med Microbiol 52(1):47–58PubMedCrossRefGoogle Scholar
  20. Huang H, Yanagisawa M, Kisanuki YY, Jelicks LA, Chandra M, Factor SM, Wittner M, Weiss LM, Pestell RG, Shtutin V, Shirani J, Tanowitz HB (2002) Role of cardiac myocyte-derived endothelin-1 in chagasic cardiomyopathy: molecular genetic evidence. Clin Sci (Lond) 103(Suppl 48):263S–266S. doi:10.1042/CS103S263S Google Scholar
  21. Huang WC, Chan ST, Yang TL, Tzeng CC, Chen CC (2004) Inhibition of ICAM-1 gene expression, monocyte adhesion and cancer cell invasion by targeting IKK complex: molecular and functional study of novel alpha-methylene-gamma-butyrolactone derivatives. Carcinogenesis 25(10):1925–1934. doi:10.1093/carcin/bgh211 PubMedCrossRefGoogle Scholar
  22. Keller TT, Mairuhu AT, de Kruif MD, Klein SK, Gerdes VE, ten Cate H, Brandjes DP, Levi M, van Gorp EC (2003) Infections and endothelial cells. Cardiovasc Res 60(1):40–48PubMedCrossRefGoogle Scholar
  23. Kenneth KW (2003) Control of COX-2 and iNOS gene expressions by aspirin and salicylate. Thromb Res 110(5–6):273–276Google Scholar
  24. Kobayashi H, Boelte KC, Lin PC (2007) Endothelial cell adhesion molecules and cancer progression. Curr Med Chem 14(4):377–386PubMedCrossRefGoogle Scholar
  25. Lannes-Vieira J, Silverio JC, Pereira IR, Vinagre NF, Carvalho CM, Paiva CN, da AA S (2009a) Chronic Trypanosoma cruzi-elicited cardiomyopathy: from the discovery to the proposal of rational therapeutic interventions targeting cell adhesion molecules and chemokine receptors—how to make a dream come true. Mem Inst Oswaldo Cruz 104(Suppl 1):226–235CrossRefGoogle Scholar
  26. Lannes-Vieira J, Silverio JC, Pereira IR, Vinagre NF, Carvalho CME, Paiva CN, da Silva AA (2009b) Chronic Trypanosoma cruzi-elicited cardiomyopathy: from the discovery to the proposal of rational therapeutic interventions targeting cell adhesion molecules and chemokine receptors—how to make a dream come true. Mem Inst Oswaldo Cruz 104:226–235PubMedCrossRefGoogle Scholar
  27. Laucella S, De Titto EH, Segura EL, Orn A, Rottenberg ME (1996) Soluble cell adhesion molecules in human Chagas’ disease: association with disease severity and stage of infection. AmJTrop Med Hyg 55(6):629–634Google Scholar
  28. Laucella SA, Segura EL, Riarte A, Sosa ES (1999) Soluble platelet selectin (sP-selectin) and soluble vascular cell adhesion molecule-1 (sVCAM-1) decrease during therapy with benznidazole in children with indeterminate form of Chagas’ disease. Clin Exp Immunol 118(3):423–427PubMedCrossRefGoogle Scholar
  29. Marin-Neto JA, Cunha-Neto E, Maciel BC, Simoes MV (2007) Pathogenesis of chronic Chagas’ heart disease. Circulation 115(9):1109–1123. doi:10.1161/CIRCULATIONAHA.106.624296 PubMedCrossRefGoogle Scholar
  30. Michelin MA, Silva JS, Cunha FQ (2005) Inducible cyclooxygenase released prostaglandin mediates immunosuppression in acute phase of experimental Trypanosoma cruzi infection. Exp Parasitol 111(2):71–79PubMedCrossRefGoogle Scholar
  31. Molina-Berrios A, Campos-Estrada C, Henriquez N, Torres G, Castillo C, Escanilla S, Kemmerling U, Morello A, Lopez-Munoz R, Maya JD (2013) Protective role of acetylsalicylic acid in experimental Trypanosoma cruzi infection: evidence of a 15-epi-Lipoxin A4-mediated effect. Plos Neglected Tropical Diseases in press. doi:10.1371/journal.pntd.0002173
  32. Morris T, Stables M, Hobbs A, de Souza P, Colville-Nash P, Warner T, Newson J, Bellingan G, Gilroy DW (2009) Effects of low-dose aspirin on acute inflammatory responses in humans. J Immunol 183(3):2089–2096. doi:10.4049/jimmunol.0900477 PubMedCrossRefGoogle Scholar
  33. Mukherjee S, Machado FS, Huang H, Oz HS, Jelicks LA, Prado CM, Koba W, Fine EJ, Zhao D, Factor SM, Collado JE, Weiss LM, Tanowitz HB, Ashton AW (2011) Aspirin treatment of mice infected with Trypanosoma cruzi and implications for the pathogenesis of Chagas’ disease. PLoS One 6(2):e16959. doi:10.1371/journal.pone.0016959 PubMedCrossRefGoogle Scholar
  34. Nagajyothi F, Machado FS, Burleigh BA, Jelicks LA, Scherer PE, Mukherjee S, Lisanti MP, Weiss LM, Garg NJ, Tanowitz HB (2012) Mechanisms of Trypanosoma cruzi persistence in Chagas disease. Cell Microbiol. doi:10.1111/j.1462-5822.2012.01764.x PubMedGoogle Scholar
  35. National Research Council (U.S.). Committee for the Update of the Guide for the Care and Use of Laboratory Animals., Institute for Laboratory Animal Research (U.S.), National Academies Press (U.S.) (2011) Guide for the care and use of laboratory animals, 8th edn. National Academies Press, Washington, D.C.Google Scholar
  36. Petkova SB, Huang H, Factor SM, Pestell RG, Bouzahzah B, Jelicks LA, Weiss LM, Douglas SA, Wittner M, Tanowitz HB (2001) The role of endothelin in the pathogenesis of Chagas’ disease. Int J Parasitol 31(5–6):499–511PubMedCrossRefGoogle Scholar
  37. Pierce JW, Read MA, Ding H, Luscinskas FW, Collins T (1996) Salicylates inhibit I kappa B-alpha phosphorylation, endothelial-leukocyte adhesion molecule expression, and neutrophil transmigration. J Immunol 156(10):3961–3969PubMedGoogle Scholar
  38. Pinazo MJ, Tassies D, Munoz J, Fisa R, Posada Ede J, Monteagudo J, Ayala E, Gallego M, Reverter JC, Gascon J (2011) Hypercoagulability biomarkers in Trypanosoma cruzi-infected patients. Thromb Haemost 106(4):617–623. doi:10.1160/TH11-04-0251 PubMedCrossRefGoogle Scholar
  39. Prado CM, Jelicks LA, Weiss LM, Factor SM, Tanowitz HB, Rossi MA (2011) The vasculature in Chagas’ disease. Adv Parasitol 76:83–99. doi:10.1016/B978-0-12-385895-5.00004-9 PubMedCrossRefGoogle Scholar
  40. Ramos SG, Rossi MA (1999) Microcirculation and Chagas’ disease: hypothesis and recent results. Rev Inst Med Trop Sao Paulo 41(2):123–129PubMedCrossRefGoogle Scholar
  41. Rassi A Jr, Rassi A, Marin-Neto JA (2010) Chagas disease. Lancet 375(9723):1388–1402. doi:10.1016/S0140-6736(10)60061-X PubMedCrossRefGoogle Scholar
  42. Ribeiro AL, Nunes MP, Teixeira MM, Rocha MO (2012) Diagnosis and management of Chagas disease and cardiomyopathy. Nat Rev Cardiol doi:10.1038/nrcardio.2012.109
  43. Rossi MA, Ramos SG (1996) Coronary microvascular abnormalities in Chagas’ disease. Am Heart J 132(1 Pt 1):207–210PubMedCrossRefGoogle Scholar
  44. Rossi MA, Tanowitz HB, Malvestio LM, Celes MR, Campos EC, Blefari V, Prado CM (2010) Coronary microvascular disease in chronic Chagas cardiomyopathy including an overview on history, pathology, and other proposed pathogenic mechanisms. PLoS Negl Trop Dis 4(8). doi:10.1371/journal.pntd.0000674
  45. Scharfstein J, Andrade D (2011) Infection-associated vasculopathy in experimental Chagas disease pathogenic roles of endothelin and kinin pathways. Adv Parasitol 76:101–127. doi:10.1016/B978-0-12-385895-5.00005-0 PubMedCrossRefGoogle Scholar
  46. Shechter M, Matetzky S, Arad M, Feinberg MS, Freimark D (2009) Vascular endothelial function predicts mortality risk in patients with advanced ischaemic chronic heart failure. Eur J Heart Fail 11(6):588–593. doi:10.1093/eurjhf/hfp053 PubMedCrossRefGoogle Scholar
  47. Soares MB, de Lima RS, Rocha LL, Vasconcelos JF, Rogatto SR, dos Santos RR, Iacobas S, Goldenberg RC, Iacobas DA, Tanowitz HB, de Carvalho AC, Spray DC (2010) Gene expression changes associated with myocarditis and fibrosis in hearts of mice with chronic chagasic cardiomyopathy. J Infect Dis 202(3):416–426. doi:10.1086/653481 PubMedCrossRefGoogle Scholar
  48. Tanowitz HB, Burns ER, Sinha AK, Kahn NN, Morris SA, Factor SM, Hatcher VB, Bilezikian JP, Baum SG, Wittner M (1990) Enhanced platelet adherence and aggregation in Chagas’ disease: a potential pathogenic mechanism for cardiomyopathy. AmJTrop Med Hyg 43(3):274–281Google Scholar
  49. Tanowitz HB, Huang H, Jelicks LA, Chandra M, Loredo ML, Weiss LM, Factor SM, Shtutin V, Mukherjee S, Kitsis RN, Christ GJ, Wittner M, Shirani J, Kisanuki YY, Yanagisawa M (2005) Role of endothelin 1 in the pathogenesis of chronic chagasic heart disease. Infect Immun 73(4):2496–2503. doi:10.1128/IAI.73.4.2496-2503.2005 PubMedCrossRefGoogle Scholar
  50. Tanowitz HB, Machado FS, Jelicks LA, Shirani J, de Carvalho AC, Spray DC, Factor SM, Kirchhoff LV, Weiss LM (2009) Perspectives on Trypanosoma cruzi-induced heart disease (Chagas’ disease). Prog Cardiovasc Dis 51(6):524–539. doi:10.1016/j.pcad.2009.02.001 PubMedCrossRefGoogle Scholar
  51. Tanowitz HB, Mukhopadhyay A, Ashton AW, Lisanti MP, Machado FS, Weiss LM, Mukherjee S (2011) Microarray analysis of the mammalian thromboxane receptor-Trypanosoma cruzi interaction. Cell Cycle 10(7):1132–1143PubMedCrossRefGoogle Scholar
  52. Vilas Boas LG, Bestetti RB, Otaviano AP, Cardinalli-Neto A, Nogueira PR (2012) Outcome of Chagas cardiomyopathy in comparison to ischemic cardiomyopathy. Int J Cardiol. doi:10.1016/j.ijcard.2012.01.033 Google Scholar
  53. Wang J, Dong S (2012) ICAM-1 and IL-8 Are Expressed by DEHP and Suppressed by Curcumin Through ERK and p38 MAPK in Human Umbilical Vein Endothelial Cells. Inflammation in press. doi:10.1007/s10753-011-9387-4

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Alfredo Molina-Berríos
    • 1
    • 4
  • Carolina Campos-Estrada
    • 1
  • Michel Lapier
    • 1
  • Juan Duaso
    • 2
  • Ulrike Kemmerling
    • 2
  • Norbel Galanti
    • 3
  • Jorge Ferreira
    • 1
  • Antonio Morello
    • 1
  • Rodrigo López-Muñoz
    • 1
  • Juan Diego Maya
    • 1
  1. 1.Molecular and Clinical Pharmacology Program, Biomedical Sciences Institute (ICBM), Faculty of MedicineUniversity of ChileSantiagoChile
  2. 2.Anatomy and Development Biology Program, Biomedical Sciences Institute (ICBM), Faculty of MedicineUniversity of ChileSantiagoChile
  3. 3.Molecular and Cellular Biology Program, Biomedical Sciences Institute (ICBM), Faculty of MedicineUniversity of ChileSantiagoChile
  4. 4.Centro de Investigación Biomédica, Facultad de MedicinaUniversidad Diego PortalesSantiagoChile

Personalised recommendations