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

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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.

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References

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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):929–940

    Article  PubMed  CAS  Google Scholar 

  • 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):517–525

    Article  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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):1282–1287

    Article  PubMed  CAS  Google Scholar 

  • 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):6017–6022

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Factor SM, Cho S, Wittner M, Tanowitz H (1985) Abnormalities of the coronary microcirculation in acute murine Chagas’ disease. AmJTrop Med Hyg 34(2):246–253

    CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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):47–58

    Article  PubMed  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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):40–48

    Article  PubMed  CAS  Google Scholar 

  • Kenneth KW (2003) Control of COX-2 and iNOS gene expressions by aspirin and salicylate. Thromb Res 110(5–6):273–276

    Google Scholar 

  • Kobayashi H, Boelte KC, Lin PC (2007) Endothelial cell adhesion molecules and cancer progression. Curr Med Chem 14(4):377–386

    Article  PubMed  CAS  Google Scholar 

  • 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):226–235

    Article  CAS  Google Scholar 

  • 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 104:226–235

    Article  PubMed  CAS  Google Scholar 

  • 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):629–634

    CAS  Google Scholar 

  • 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):423–427

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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):71–79

    Article  PubMed  CAS  Google Scholar 

  • 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

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • 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 

  • 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):499–511

    Article  PubMed  CAS  Google Scholar 

  • 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):3961–3969

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Ramos SG, Rossi MA (1999) Microcirculation and Chagas’ disease: hypothesis and recent results. Rev Inst Med Trop Sao Paulo 41(2):123–129

    Article  PubMed  CAS  Google Scholar 

  • Rassi A Jr, Rassi A, Marin-Neto JA (2010) Chagas disease. Lancet 375(9723):1388–1402. doi:10.1016/S0140-6736(10)60061-X

    Article  PubMed  Google Scholar 

  • 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

  • Rossi MA, Ramos SG (1996) Coronary microvascular abnormalities in Chagas’ disease. Am Heart J 132(1 Pt 1):207–210

    Article  PubMed  CAS  Google Scholar 

  • 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

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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):274–281

    CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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):1132–1143

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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

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Acknowledgments

This work was supported by grants from Fondo Nacional de Ciencia y Tecnología Chile (Grant numbers 1090078, 1120230, and 1090124) and a grant from Consejo Nacional de Ciencia y Tecnologia—Programa de Investigacion Asociativa Chile (Grant Anillo ACT112). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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The authors declare that they have no conflict of interest.

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Correspondence to Rodrigo López-Muñoz or Juan Diego Maya.

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Molina-Berríos, A., Campos-Estrada, C., Lapier, M. et al. Protection of vascular endothelium by aspirin in a murine model of chronic Chagas’ disease. Parasitol Res 112, 2731–2739 (2013). https://doi.org/10.1007/s00436-013-3444-x

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