Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Inhibition of ER Stress by 2-Aminopurine Treatment Modulates Cardiomyopathy in a Murine Chronic Chagas Disease Model

  • Ayyappan, Janeesh Plakkal (Department of Microbiology, Biochemistry and Molecular Genetics, Public Health Research Institute, New Jersey Medical School) ;
  • lizardo, Kezia (Department of Microbiology, Biochemistry and Molecular Genetics, Public Health Research Institute, New Jersey Medical School) ;
  • Wang, Sean (Rutgers Molecular Imaging Center) ;
  • Yurkow, Edward (Rutgers Molecular Imaging Center) ;
  • Nagajyothi, Jyothi F (Department of Microbiology, Biochemistry and Molecular Genetics, Public Health Research Institute, New Jersey Medical School)
  • Received : 2018.10.02
  • Accepted : 2019.01.25
  • Published : 2019.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

Trypanosoma cruzi infection results in debilitating cardiomyopathy, which is a major cause of mortality and morbidity in the endemic regions of Chagas disease (CD). The pathogenesis of Chagasic cardiomyopathy (CCM) has been intensely studied as a chronic inflammatory disease until recent observations reporting the role of cardio-metabolic dysfunctions. In particular, we demonstrated accumulation of lipid droplets and impaired cardiac lipid metabolism in the hearts of cardiomyopathic mice and patients, and their association with impaired mitochondrial functions and endoplasmic reticulum (ER) stress in CD mice. In the present study, we examined whether treating infected mice with an ER stress inhibitor can modify the pathogenesis of cardiomyopathy during chronic stages of infection. T. cruzi infected mice were treated with an ER stress inhibitor 2-Aminopurine (2AP) during the indeterminate stage and evaluated for cardiac pathophysiology during the subsequent chronic stage. Our study demonstrates that inhibition of ER stress improves cardiac pathology caused by T. cruzi infection by reducing ER stress and downstream signaling of phosphorylated eukaryotic initiation factor ($P-elF2{\alpha}$) in the hearts of chronically infected mice. Importantly, cardiac ultrasound imaging showed amelioration of ventricular enlargement, suggesting that inhibition of ER stress may be a valuable strategy to combat the progression of cardiomyopathy in Chagas patients.

Keywords

References

  1. B'chir, W., Maurin, A. C., Carraro, V., Averous, J., Jousse, C., Muranishi, Y., Parry, L., Stepien, G., Fafournoux, P. and Bruhat, A. (2013) The eIF2${\alpha}$/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 41, 7683-7699. https://doi.org/10.1093/nar/gkt563
  2. Cao, S. S. and Kaufman, R. J. (2014) Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid. Redox Signal. 21, 396-413. https://doi.org/10.1089/ars.2014.5851
  3. Carpio, M. A., Michaud, M., Zhou, W., Fisher, J. K., Walensky, L. D. and Katz, S. G. (2015) BCL-2 family member BOK promotes apoptosis in response to endoplasmic reticulum stress. Proc. Natl. Acad. Sci. U.S.A. 112, 7201-7206. https://doi.org/10.1073/pnas.1421063112
  4. Combs, T. P., Mukherjee, S., De Almeida, C. J., Jelicks, L. A., Schubert, W., Lin, Y., Jayabalan, D. S., Zhao, D., Braunstein, V. L., Landskroner-Eiger, S., Cordero, A., Factors, S. M., Weiss, L. M., Lisanti, M. P., Tanowitz, H. B. and Scherer, P. E. (2005) The adipocyte as an important target cell for Trypanosoma cruzi infection. J. Biol. Chem. 280, 24085-24094. https://doi.org/10.1074/jbc.M412802200
  5. Fernandas, O., Santos, S. S., Cupolillo, E., Mendonça, B., Derre, R., Junqueira, A. C. V., Santos, L. C., Sturm, N. R., Naiff, R. D., Barret, T. V. and Campbell, D. A. (2001) A mini-exon multiplex polymerase chain reaction to distinguish the major groups of Trypanosoma cruzi and T. rangeli in the Brazilian Amazon. Trans. R. Soc. Trop. Med. Hyg. 95, 97-99. https://doi.org/10.1016/S0035-9203(01)90350-5
  6. Feng, C. Y. and Rise, M. L. (2010) Characterization and expression analyses of anti-apoptotic Bcl-2-like genes NR-13, Mcl-1, Bcl-X1 and Bcl-X2 in Atlantic cod (Gadus morhua). Mol. Immunol. 47, 763-784. https://doi.org/10.1016/j.molimm.2009.10.011
  7. Gardner, B. M., Pincus, D., Gotthardt, K., Gallagher, C. M. and Walter, P. (2013) Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb. Perspect. Biol. 5, a013169. https://doi.org/10.1101/cshperspect.a013169
  8. Garg, N., Popov, V. L. and Papaconstantinou, J. (2003) Profiling gene transcription reveals a deficiency of mitochondrial oxidative phosphorylation in Trypanosoma cruzi-infected murine hearts: implications in chagasic myocarditis development. Biochim. Biophys. Acta 1638, 106-120. https://doi.org/10.1016/S0925-4439(03)00060-7
  9. Gupta, S., Wen, J. J. and Garg, N. J. (2009) Oxidative stress in Chagas disease. Interdiscip. Perspect. Infect. Dis. 2009, 190354.
  10. Han, J. and Kaufman, R. J. (2016) The role of ER stress in lipid metabolism and lipotoxicity. J. Lipid Res. 57, 1329-1338. https://doi.org/10.1194/jlr.R067595
  11. Harding, H.P., Zhang, Y., Bertolotti, A., Zeng, H. and Ron, D. (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol. Cell 5, 897-904. https://doi.org/10.1016/S1097-2765(00)80330-5
  12. Jacquemyn, J., Cascalho, A. and Goodchild, R. E. (2017) The ins and outs of endoplasmic reticulum-controlled lipid biosynthesis. EMBO Rep. 18, 1905-1921. https://doi.org/10.15252/embr.201643426
  13. Jelicks, L. A. and Tanowitz, H. B. (2011) Advances in imaging of animal models of Chagas disease. Adv. Parasitol. 75, 193-208. https://doi.org/10.1016/B978-0-12-385863-4.00009-5
  14. Jelicks, L. A., Chandra, M., Shtutin, V., Tang, B., Christ, G. J., Factor, S. M., Wittner, M., Huang, H., Douglas, S. A., Weiss, L. M., Orleans-Juste P. D., Shirani J. and Tanowitz H. B. (2002) Phosphoramid on treatment improves the consequences of chagasic heart disease in mice. Clin. Sci. (Lond.) 103, 267S-271S. https://doi.org/10.1042/CS103S267S
  15. Johndrow, C., Nelson, R., Tanowitz, H., Weiss, L. M. and Nagajyothi, F. (2014) Trypanosoma cruzi infection results in an increase in intracellular cholesterol. Microbes Infect. 16, 337-344. https://doi.org/10.1016/j.micinf.2014.01.001
  16. Kezia, L., Janeesh, P. A., Cui, M. H., Rashmi B., Jelicks, L. A. and Nagajyothi, F. (2018) High fat diet aggravates cardiomyopathy in murine chronic Chagas disease. Microbes Infect. 18, 1286-4579.
  17. Li, X., Zhao, D., Guo, Z., Li, T., Qili, M., Xu, B., Qian, M., Liang, H., Xiaoqiang, E., Gitau, S. C., Wang, L., Huangfu, L., Wu, Q., Xu, C. and Shan, H. (2016) Overexpression of SerpinE2/protease nexin-1 contribute to pathological cardiac fibrosis via increasing collagen deposition. Sci. Rep. 6, 37635. https://doi.org/10.1038/srep37635
  18. Lipskaia, L., Chemaly, E. R., Hadri, L., Lompre, A. M. and Hajjar, R. J. (2010) Sarcoplasmic reticulum Ca2+ ATPase as a therapeutic target for heart failure. Expert Opin. Biol. Ther. 10, 29-41. https://doi.org/10.1517/14712590903321462
  19. Machado, F. S., Jelicks, L. A., Kirchhoff, L. V., Shirani, J., Nagajyothi, F., Mukherjee, S., Nelson, R., Coyle, C. M., Spray, D. C., de Carvalho, A. C., Guan, F., Prado, C. M., Lisanti, M. P., Weiss, L. M. Montgomery, S. P. and Tanowitz, H. B. (2012) Chagas heart disease: report on recent developments. Cardiol. Rev. 20, 53-65. https://doi.org/10.1097/CRD.0b013e31823efde2
  20. Malhotra, J. D. and Kaufman, R. J. (2007) The endoplasmic reticulum and the unfolded protein response. Semin. Cell Dev. Biol. 18, 716-731. https://doi.org/10.1016/j.semcdb.2007.09.003
  21. Memorial, C. C. (2009) Chagas disease and its toll on the heart. Eur. Heart J. 30, 2063-2072. https://doi.org/10.1093/eurheartj/ehp277
  22. Minning, T. A., Weatherly, D. B., Flibotte, S. and Tarleton, R. L. (2011) Widespread, focal copy number variations (CNV) and whole chromosome aneuploidies in Trypanosoma cruzi strains revealed by array comparative genomic hybridization. BMC Genomics 12, 139-150. https://doi.org/10.1186/1471-2164-12-139
  23. Nagajyothi, F., Weiss, L. M., Zhao, D., Koba, W., Jelicks, L. A., Cui, M. H., Factor, S. M., Scherer, P. E. and Tanowitz, H. B. (2014) High fat diet modulates Trypanosoma cruzi infection associated myocarditis. PLoS Negl. Trop. Dis. 8, e3118. https://doi.org/10.1371/journal.pntd.0003118
  24. Nunes, M. C. P., Dones, W., Morillo, C. A., Encina, J. J. and Ribeiro, A. L. (2013) Chagas disease: an overview of clinical and epidemiological aspects. J. Am. Coll. Cardiol. 62, 767-776. https://doi.org/10.1016/j.jacc.2013.05.046
  25. Quijano-Hernandez, I. and Dumonteil, E. (2011) Advances and challenges towards a vaccine against Chagas disease. Hum. Vaccin. 7, 1184-1191. https://doi.org/10.4161/hv.7.11.17016
  26. Rozpedek, W., Pytel, D., Mucha, B., Leszczynska, H., Diehl, J. A. and Majsterek, I. (2016) The role of the PERK/eIF2${\alpha}$/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Curr. Mol. Med. 16, 533-544. https://doi.org/10.2174/1566524016666160523143937
  27. Soares, M. B. P., De Lima, R. S., Rocha, L. L., Vasconcelos, J. F., Rogatto, S. R., Dos Santos, R. R., Iacobas, S., Goldenberg, R. C., Iacobas, D. A., Tanowitz, H. B., de Carvalho, A. C. and Spray, D. C. (2010) Gene expression changes associated with myocarditis and fibrosis in hearts of mice with chronic chagasic cardiomyopathy. J. Infect. Dis. 202, 416-426. https://doi.org/10.1086/653481
  28. Tanowitz, H. B., Kirchhoff, L. V., Simon, D., Morris, S. A., Weiss, L. M. and Wittner, M. (1992) Chagas' disease. Clin. Microbiol. Rev. 5, 400-419. https://doi.org/10.1128/CMR.5.4.400
  29. Tostes, S., Bertulucci, D., Pereira, G. and Rodrigues. V. (2005) Myocardiocyte apoptosis in heart failure in chronic Chagas' disease. Int. J. Cardiol. 99, 233-237. https://doi.org/10.1016/j.ijcard.2004.01.026
  30. Van Kerckhoven, R., Kalkman, E. A., Saxena, P. R. and Schoemaker, R. G. (2000) Altered cardiac collagen and associated changes in diastolic function of infarcted rat hearts. Cardiovasc. Res. 46, 316-323. https://doi.org/10.1016/S0008-6363(99)00427-7
  31. Volmer, R. and Ron, D. (2015) Lipid-dependent regulation of the unfolded protein response. Curr. Opin. Cell Biol. 33, 67-73. https://doi.org/10.1016/j.ceb.2014.12.002
  32. Weber, G. F. and Menko, A. S. (2005) The canonical intrinsic mitochondrial death pathway has a non-apoptotic role in signaling lens cell differentiation. J. Biol. Chem. 280, 22135-22145. https://doi.org/10.1074/jbc.M414270200
  33. Westphal, D., Dewson, G., Czabotar, P. E. and Kluck, R. M. (2011) Molecular biology of Bax and Bak activation and action. Biochim. Biophys. Acta 1813, 521-531. https://doi.org/10.1016/j.bbamcr.2010.12.019
  34. Zhao, L. and Ackerman, S. L. (2006) Endoplasmic reticulum stress in health and disease. Curr. Opin. Cell Biol. 18, 444-452. https://doi.org/10.1016/j.ceb.2006.06.005
  35. Zhou, L., Yang, D., Wu, D. F., Guo, Z. M., Okoro, E. and Yang, H. (2013) Inhibition of endoplasmic reticulum stress and atherosclerosis by 2-aminopurine in apolipoprotein e-deficient mice. ISRN Pharmacol. 2013, 847310. https://doi.org/10.1155/2013/847310

Cited by

  1. NOD1 and NOD2 Activation by Diverse Stimuli: a Possible Role for Sensing Pathogen-Induced Endoplasmic Reticulum Stress vol.88, pp.7, 2019, https://doi.org/10.1128/iai.00898-19
  2. Endoplasmic Reticulum Stress, a Target for Drug Design and Drug Resistance in Parasitosis vol.12, 2019, https://doi.org/10.3389/fmicb.2021.670874
  3. Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles vol.17, pp.2, 2019, https://doi.org/10.1080/15548627.2020.1725377
  4. Fat tissue regulates the pathogenesis and severity of cardiomyopathy in murine chagas disease vol.15, pp.4, 2019, https://doi.org/10.1371/journal.pntd.0008964