Interdisciplinary Perspectives on Infectious Diseases

Interdisciplinary Perspectives on Infectious Diseases / 2009 / Article
Special Issue

Parasitic Diseases, Diagnostic Approaches, and Therapies

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Review Article | Open Access

Volume 2009 |Article ID 190354 |

Shivali Gupta, Jian-Jun Wen, Nisha Jain Garg, "Oxidative Stress in Chagas Disease", Interdisciplinary Perspectives on Infectious Diseases, vol. 2009, Article ID 190354, 8 pages, 2009.

Oxidative Stress in Chagas Disease

Academic Editor: Herbert B. Tanowitz
Received19 Mar 2009
Accepted23 Apr 2009
Published14 Jun 2009


There is growing evidence to suggest that chagasic myocardia are exposed to sustained oxidative stress induced injuries that may contribute to disease progression. Trypanosoma cruzi invasion- and replication-mediated cellular injuries and immune-mediated cytotoxic reactions are the common source of reactive oxygen species (ROS) during acute infection. Mitochondria are proposed to be the major source of ROS in chronic chagasic hearts. However, it has not been established yet, whether mitochondrial dysfunction is a causative factor in chagasic cardiomyopathy or a consequence of other pathological events. A better understanding of oxidative stress in relation to cardiac tissue damage would be useful in the evaluation of its true role in the pathogenesis of Chagas disease and other heart diseases. In this review, we discuss the evidence for increased oxidative stress in chagasic disease, with emphasis on mitochondrial abnormalities, and its role in sustaining oxidative stress in myocardium.

1. Chagas Disease

Chagas disease continues to pose a serious threat to health in Latin America and Mexico, and is the most important emerging parasitic disease in developed countries. According to the World Health Organization, the overall prevalence of human Trypanosoma cruzi infection is at ~16–18 million cases, and ~120 million people are at risk of infection in Latin America [1]. In most patients, the early period of T. cruzi infection goes virtually unnoticed whereas others develop an acute phase that lasts several weeks and is accompanied by such nonspecific symptoms, fever, tachycardia, weakness, and lymphadenopathy [2, 3]. After acute control of T. cruzi, infected patients enter an indeterminate phase, defined by the absence of clinical symptoms although subclinical pathology may be present. Unfortunately, 15–30 years after the initial infection, 30–40% of the infected patients develop life threatening dilated cardiomyopathy associated with clinical symptoms of ventricular dilation, arrhythmia, and cardiac arrest [4]. The pathological developments and clinical symptoms vary widely among chagasic patients [2, 57]. Not every individual infected with T. cruzi experiences the abnormalities characteristic of the three phases of Chagas disease: acute, indeterminate, and chronic. These facts make Chagas disease a complex disease and difficult to understand.

Over the years, a number of mechanisms have been proposed to explain the pathogenesis of Chagas disease (reviewed in [8, 9]). There is growing evidence to suggest that chagasic myocardia are exposed to sustained oxidative stress-induced injuries that may contribute to disease progression. In this review, we discuss the evidence for increased oxidative stress in chagasic disease, with emphasis on mitochondrial abnormalities, as well as electron transport chain dysfunction, and its role in sustaining oxidative stress in myocardium.

2. Sources of Oxidants

2.1. Overview

Broadly defined, reactive oxygen species (ROS, e.g., , , and ) are derivatives of molecular oxygen. ROS are unstable and react rapidly with other free radicals and macromolecules in chain reactions to generate increasingly harmful oxidants. ROS are produced through the action of specific oxidases and oxygenases (e.g., xanthine oxidase, and NADPH oxidase), peroxidases (e.g., myeloperoxidase), the Fenton reaction, and are also by-products of the electron transport chain of mitochondria [10]. Nitric oxide ( ) is produced by the enzymatic activity of nitric oxide synthases (NOS), which oxidize L-arginine, transferring electrons from NADPH. Different NOS isoforms have been identified, for example, inducible NOS (iNOS) in phagocytic cells, mtNOS in mitochondria, (eNOS) in endothelial cells, and neuronal nNOS [11].

2.2. ROS in Chagasic Hosts

During the course of T. cruzi infection and disease development, ROS can be produced as a consequence of tissue destruction caused by toxic secretions of parasite, immune-mediated cytotoxic reactions, and secondary damage to mitochondria.

In experimental studies, T. cruzi infection has been suggested to initiate ROS formation via the stimulation of inflammatory mediators, for example, cytokines and chemokines, which lead to an oxidative burst of phagocytic cells. Several investigators have used in vitro assay systems or animal models and demonstrated that T. cruzi-mediated macrophage activation results in increased levels of formation, likely by the NADPH oxidase-dependent oxidative burst [1214]. In addition to ROS, activated macrophages can produce large amounts of by iNOS. Accordingly, TNF- - and IFN- -dependent increased iNOS expression and production is noted in splenocytes of T. cruzi-infected mice [15] and in macrophages infected in vitro with T. cruzi [16]. We have found increased levels of myeloperoxidase and nitrite in the plasma of T. cruzi-infected mice [17] that are markers of neutrophil and macrophage activation, respectively. Relatively few studies have been performed to elucidate inflammatory oxidative stress in human patients. In humans, the severity of cardiac disease was correlated with high plasma levels of TNF- and [18]. The level was also increased in indeterminate individuals in comparison to healthy controls [19]. These reactive oxidants are important for the control of T. cruzi, and may elicit toxicity to host cellular components.

Recent studies provide evidence for enhanced mitochondrial ROS generation ( and ) in chagasic myocardium. Mitochondria are the prime source of energy and many of the body’s functions, including those of cardiac metabolic and contractile activities, require mitochondrial generation of ATP. Electron microscopic analysis of heart biopsies from chagasic patients and experimental animals have shown that with disease development, mitochondrial degenerative changes, that is, swelling, irregular membranes, and loss of cristae, accrue in the heart with disease development [2023]. Global microarray profiling of gene expression has identified alterations in several of the mitochondrial function related transcripts in the myocardium of infected humans [24] and experimental animals [25, 26]. The biochemical evidence for the mitochondrial dysfunction was provided by documentation of a decline in the activities of respiratory complexes, NADH-ubiquinone reductase (CI) and ubiquinol-cytochrome c reductase (CIII) [27] and ATP synthase (CV) complex [28] in chagasic murine hearts. The functional effect of these perturbations was shown by decreased mitochondrial respiration [29], and reduction in myocardial and mitochondrial ATP levels [30] in chagasic experimental models.

Imperatively, mitochondrial dysfunction also contributes to increased oxidative stress. A low, but constant, production of superoxide occurs in mitochondria. The rate of electron leakage and formation in mitochondria is closely related to the coupling efficiency between the respiratory chain and oxidative phosphorylation [31]. The CI and CIII complexes are the main sites for electron leakage to O2 and generation in mitochondria [32, 33]. We have shown a decline in complex I and complex III activities in the myocardium was associated with excessive leakage of electrons to molecular oxygen and sustained ROS production in chagasic mice [27]. Further studies identified that CI was not the main source of increased ROS in chagasic hearts. Instead, defects of the myxothiazol-binding site in CIII complex resulted in enhanced electron leakage towards the Qo-center, and contributed to increased ROS generation in chagasic cardiac mitochondria [34]. Thus, conditions conducive to oxidative stress are presented in the Chagasic heart.

3. Antioxidants

3.1. Overview

The overall level of cellular ROS and its biological effects are determined by the relative rates of ROS generation and the rate of reduction by antioxidants. The principal enzymatic antioxidants are superoxide dismutase (SOD), catalase (CAT), peroxiredoxin (Prx), and glutathione peroxidase (GPx). These enzymes work in tandem to scavenge ROS. SOD exists in different isoforms, for example, manganese SOD (MnSOD) in the mitochondrial matrix and Cu- or Zn-SOD in the cytoplasm, mitochondria intermembrane space, and endothelial cell surface [35]. SOD converts to [36]. CAT, located in peroxisomes, converts to H2O and O2 [37]. Prx reduces peroxides, including and alkyl hydroperoxides [38]. The five isoforms of GPx utilize glutathione (GSH), and reduce or lipid peroxides (ROOH) to H2O or alcohols (ROH), respectively. The byproduct of this reaction, GSSG is recycled by glutathione S reductase [38]. The nonenzymatic antioxidants, for example, vitamin E ( -tocopherol) and vitamin C (ascorbate), are abundant in aerobic organisms. Vitamin E, active in membranes, functions to reduce peroxy radicals. Vitamin C, a highly soluble antioxidant in plasma, functions by reducing -tocopherol-lipid peroxide radicals, particularly formed in reaction with the low-density lipoproteins (LDL) [37].

3.2. Antioxidant Status in Chagasic Host

The myocardium contains high concentrations of various nonenzymatic antioxidants such as reduced glutathione (GSH) and vitamins A, C, and E, and enzymatic scavengers of ROS, including GPx and Mn- and CuZn-SOD. GSH, GPx, and MnSOD are shown to be most critical in cardiac antioxidant defenses, particularly in protecting the cardiomyocytes from oxidative injury [39, 40]. We and others have evaluated the antioxidant/oxidant balance in experimental models of chagasic disease and human patients. Our experimental studies showed that the host responds to acute T. cruzi infection by upregulating glutathione antioxidant defense constituted by GPx, GSR, and GSH. However, after the initial burst, the glutathione defense was unresponsive to chronic oxidative stress, and the cardiac levels of GSH and MnSOD were significantly diminished in chagasic mice [41]. A decline in plasma levels of GSH, the GSH/GSSG ratio [42, 43], and GPx activity [18], along with decreased MnSOD activity in PBMCs of seropositive chagasic patients [42, 43] is also noted. Decreased antioxidant levels (GPx and SOD) were correlated with an increase in TNF- and NO levels in human patients [18]. All of these observations suggest an antioxidant response is not sufficiently activated to scavenge the ROS during progressive chagasic disease.

4. Cytotoxicity of Oxidative Stress

4.1. Overview

ROS and , when produced in physiological quantities, play critical roles in normal developmental processes, and control signal transduction mechanisms that regulate cell proliferation, differentiation, and death [44, 45]. However, when ROS are produced in excess or for sustained periods, they may exert toxic effects that damage cells and tissues, thereby resulting in dysfunction of physiological processes. ROS can rapidly oxidize proteins, lipids, and DNA. Lipid peroxidation causes damage to membrane integrity and loss of membrane protein function. Specifically, 4-hydroxynonenal (HNE) and malonyldialdehyde (MDA) are products of the peroxidation of membrane phospholipids [4648]. These oxidized lipids are also toxic because they are highly reactive species that result in oxidative modification of proteins [37]. For example, HNE reacts with Cys, His, or Lys residues via a Michael addition that results in irreversible alkylation and introduction of carbonyl groups into proteins [49]. The direct oxidative attack by ROS on Arg, Lys, Pro, and Thr residues can also derivatize the proteins and lead to the formation of protein carbonyls [50, 51]. reacts with , to form peroxynitrite ( ). Myeloperoxidase-dependent oxidation of nitrite (NO2) results in formation of nitrogen dioxide (NO2) and nitryl chloride (NO2Cl). These reactive nitrogen species (RNS) result in protein tyrosine nitration that is widely recognized as a hallmark of nitrosative stress and inflammation [52]. Because of oxidation or nitration, a functional impairment of proteins occurs, and furthermore leads to protein turnover, for example, degradation by proteases via the proteosome [53]. DNA can be oxidized by a variety of mechanisms, resulting in nucleotide damage, for example, formation of 8-oxoguanine lesions. As a result, DNA replication may be inaccurate leading to mutations and transcription errors. While mechanisms exist to repair these DNA lesions, the level of DNA damage may exceed the capacity of the cellular repair mechanisms. Furthermore, mtDNA is believed to be particularly susceptible to sustained damage, since mitochondria may lack appropriate DNA repair mechanisms [54].

4.2. Oxidative Damage in Chagas Disease

Oxidative stress-induced injuries are a common finding in chagasic myocardium. T. cruzi has the potential to infect a wide range of host tissues [55]. As discussed above, the inflammatory infiltrate in acutely infected host is mainly constituted of phagocytic cells (e.g., macrophages) and neutrophils that produce ROS/RNS through oxidative burst [56], iNOS-dependent release [15], and myeloperoxidase-dependent HOCl production [57]. Oxidative damage is a consequence of the extent of oxidative stress and the antioxidant capacity. A T. cruzi-infected host does respond to inflammatory oxidative stress by an upregulation of antioxidant response constituted of GPx, GSH, and GST [41]. Yet, oxidative cellular damage, evidenced by increased protein carbonyls, MDA, and GSSG levels, is widespread, and associated with the presence of parasite foci and inflammatory infiltrate in the heart, as well as in other muscle tissues in acutely infected mice [58]. The acute oxidative damage, thus, appears to be a bystander effect of inflammatory responses elicited by T. cruzi, and occurs in all muscle tissues.

The immune control of acute parasitemia fails to provide sterile immunity. The evolution of a chronic phase is associated with mild-to-moderate diffused inflammation in different tissues and organs. It would be an oversimplification to suggest that cardiac pathology is merely an outcome of infection and inflammation, or parasite persistence that is sufficient to drive an ongoing host immune response targeted against T. cruzi. An unvarying high degree of oxidative damage persists mainly in the myocardium of chronically infected mice, as evidenced by high levels of MDA, protein carbonyl, and GSSG contents in the heart compared to findings in the skeletal muscle and colon tissue [58]. We propose the persistent activation of oxidative injurious processes plays an important role in heart-specific tissue damage in Chagas disease.

Several observations led us to consider that ROS in chronic chagasic heart are primarily produced by dysfunctional mitochondria. It is well known that ROS are generated at several subcellular sites [59] and particularly in mitochondria [60]. In effect, ~2% of the O2 consumed by mitochondria is converted to due to spontaneous electron leaks from the respiratory chain [61]. Activated skeletal and intestinal muscles intermittently require mitochondria as an energy source, while cardiomyocytes are constantly dependent upon mitochondrial functions for their energy requirement for maintaining the contractile and other metabolic activities. According to energy demand, a ~30% cell volume of cardiomyocytes is provided by mitochondria, while in other tissues mitochondria constitute only 3–6% of cell volume [62]. Thus, maximal O2 consumption, as would be expected based upon the number of mitochondria in the heart, would produce substantial in the heart through electron leakage from the respiratory chain. Thus, it can be inferred that even in normal conditions, heart tissue is maximally exposed to ROS of mitochondrial origin. Besides this, inefficient functioning of the respiratory complexes, as documented in chagasic hearts [27], would result in an inadequate coupling of the respiratory chain with oxidative phosphorylation and an excessive release of electrons to molecular oxygen, leading to an increased mitochondrial ROS production. We have recently found that the rate of mitochondrial generation was substantially increased in cardiac tissue of infected mice [34], and associated with the oxidation of several subunits of the respiratory complexes [41]. The active-site thiol and heme proteins within respiratory complexes are particularly vulnerable to ROS [63]. The oxidative modification/degradation of heme proteins of the complexes release iron, the catalyst of the Fenton reaction, resulting in the formation/release of radicals [6466]. Taken together, these observations suggest that, under disease conditions, mitochondria are vulnerable to oxidative stress, as well as to becoming the site of an increasing order of ROS production. We, thus, propose that the acute inflammatory oxidative stress-induced mitochondrial injuries initiate a feedback cycle of ROS production and oxidative overload that causes sustained oxidative damage in the myocardium. A compromise in mitochondrial antioxidant enzyme activity (MnSOD) in chagasic myocardium would further exacerbate the mitochondrial ROS toxicity. The foregoing studies have pointed to the pathologic significance of oxidative responses in Chagasic cardiomyopathy.

It is important to note that a high degree of oxidative stress is detected in the peripheral blood of chagasic mice [58]. The demonstration of a strong positive correlation in the heart-versus-blood levels of oxidative stress markers (MDA and GSSG), and antioxidants (SOD, MnSOD, and catalase), and the mitochondrial inhibition of respiratory complexes in chronically infected mice have made it apparent that peripheral blood will be useful for understanding the role of mitochondrial decay and oxidative stress in the initiation and progression of human chagasic disease.

Subsequently, observations of increased plasma levels of GSSG and MDA and a decline in GPx activity in seropositive humans [18, 42] have led to the suggestion that chagasic patients are indeed exposed to an antioxidant/oxidant imbalance. As in experimental studies, multiple mechanisms are likely to contribute to increased oxidative stress-induced damage in chagasic patients. Plasma levels of inflammatory cytokines, [18] and myeloperoxidase activity [17] are increased in seropositive subjects which seems to imply that the cytotoxic effects of free radicals released by immune cells would contribute to oxidative pathology in chagasic patients. The increase in plasma MDA levels in chagasic patients may also be due to oxidatively modified lipids released as a consequence of cellular injuries, most likely, that are incurred in the cardiac tissue. This notion is supported by the observation of intense myocardial oxidative modifications [41] associated with the detection of oxidatively modified lipids and proteins in the serum [58] of mice infected by T. cruzi. Additionally, SOD and glutathione (GPx-GSH-GR) antioxidant defenses, utilized by mammalian cells to cope with free radicals [67], are found to be compromised in chagasic patients [18, 42]. These observations support the idea that glutathione antioxidant defenses, despite being active, may only be partially effective in balancing the oxidant level in chagasic patients.

5. Antioxidant Adjunct Therapy

Interventions that reduce the generation or the effects of ROS may exert beneficial effects in preventing or arresting oxidative damage. Several therapeutic interventions, for example, a vitamin E-like antioxidant, an SOD mimetic [68, 69], and an decomposition catalyst [70] have been examined for their beneficial effects against ROS in different systems. Phenyl-N-tert-butylnitrone (PBN), a nitrone-based compound, is a potent antioxidant. PBN has been shown to trap or scavenge a wide variety of free radical species, including biologically relevant and hydroxyl radicals; to increase endogenous antioxidant levels; and to inhibit free radical generation [71]. In addition, PBN has been shown to inhibit the expression of a variety of inflammation-associated gene products [72].

In a recent study, we have shown that PBN treatment of infected mice prevented an oxidative stress-mediated loss in mitochondrial membrane integrity; preserved redox potential coupled with mitochondrial gene expression, and improved respiratory complex activities in infected myocardium [30]. Importantly, the PBN-mediated normalization of respiratory complex activities led to the inhibition of a feedback cycle of electron transport chain inefficiency, increased ROS production, and energy homeostasis in acute chagasic hearts [30]. Others have shown a decline in oxidative stress in human chagasic patients given Vitamin A [73]. We propose that antioxidants capable of modulating or delaying the onset of oxidative insult and mitochondrial deficiencies in the myocardium would prove to be useful in preserving cardiac functions in Chagas disease.

6. Ischemic Injury and ROS

Approximately 10% of chronic chagasic patients exhibit signs of ischemic disease [74, 75]. The abnormalities during isovolemic contraction and the early relaxation phase, in general ascribed to asynchronous onset of contraction, are noted in chagasic patients, and are similar to that seen in patients with conventional ischemic heart disease of other etiologies [76]. Others have suggested the alterations in the coronary microcirculation contribute to ischemic tissue damage in chronic chagasic patients [75, 7780]. Myocardial hypoperfusion owing to an affected microvasculature has also been noted in chagasic heart regions with normal or mildly impaired wall motion [75, 80].

Hypoxia is a critical outcome of ischemia. In hypoxic tissues, low availability of oxygen results in electron accumulation in highly reduced respiratory complexes that lead to severely compromised respiration and ATP synthesis [8183]. Ischemia also influences mitochondrial function via change in calcium flux [84], cyt c depletion (reviewed in [85]), and decline in intrinsic level of MnSOD—the mtROS scavenger [86]. The inefficient scavenging of mtROS during hypoxia is complemented by increased production of ROS at reperfusion [87]. Mitochondrial loss of cyt c is considered to potentate ROS production at reperfusion because (a) cyt c is a catalytic scavenger for mitochondrial , and (b) loss of cyt c results in highly reduced state of respiratory complexes I, II, and III, thus, favoring electron release to molecular oxygen and production [88, 89]. These observations suggest that mitochondrial inhibition of respiration and ATP synthesis resulting from hypoxia, coupled with an increase in formation and ROS-induced injurious effects during reperfusion, potentially contribute to the contractile dysfunction and cell death in Chagasic hearts, to be confirmed in future studies.

7. Summary

Sustained ROS generation of inflammatory and mitochondrial origin, coupled with an inadequate antioxidant response, result in the inefficient scavenging of ROS in the heart, and lead to long-term oxidative stress, and subsequently, to oxidative damage of the cardiac cellular components during chagasic disease. The alterations in biomarkers of oxidant and antioxidant status and in respiratory complex activities in the heart and blood/plasma of infected host appear to have same pathologic tendencies, which led to the suggestion that peripheral blood would be a useful tissue for investigating the pathologic importance of impaired mitochondrial function and oxidant/antioxidant status in chagasic disease development. Further studies should examine the pathological relevance of oxidative stress in clinical severity of chronic heart disease in Chagasic patients.


CI:NADH ubiquinone oxidoreductase
CII:Succinate decylubiquinone 2, 6 dichlorophenolindophenolreductase
CIII:Ubiquinol cytochrome c oxidoreductase
CIV:Cytochrome c oxidase
cyt c:Cytochrome c
GPx:Glutathione peroxidase
NADH:Nicotinamide adenine dinucleotide (reduced form)
NOS:Nitric oxide synthase
ROS:Reactive oxygen species
SOD:Superoxide dismutase
T. cruzi:Trypanosoma cruzi.


The work discussed in this review was supported by Grants from the National Heart, Lung, and Blood Institute (HL088320 and HL094802) and the National Institutes of Allergy and Infectious Diseases (AI053098 and AI054578) of the National Institutes of Health, John Sealy Memorial Endowment Fund for Biomedical Research, and the American Health Assistance Foundation. The authors also would like to thank Ms. Mardelle Susman for editing the manuscript.


  1. World Health Organization, “Report of the scientific working group on chagas disease,” Tech. Rep., UNDP/World Bank/WHO, Buenos Aires, Argentina, 2006. View at: Google Scholar
  2. Z. Brener, “Present status of chemotherapy and chemoprophylaxis of human trypanosomiasis in the Western Hemisphere,” Pharmacology & Therapeutics, vol. 7, no. 1, pp. 71–90, 1979. View at: Publisher Site | Google Scholar
  3. J. Milei and R. Storino, “Early myocardial infarction. A feasible histologic diagnostic procedure,” Japanese Heart Journal, vol. 27, no. 3, pp. 307–319, 1986. View at: Google Scholar
  4. C. A. Santos-Buch and A. M. Acosta, “Pathology of Chagas' disease,” in Immunology and Pathology of Trypanosomiasis, I. Tizard, Ed., pp. 145–183, CRC Press, Boca Raton, Fla, USA, 1985. View at: Google Scholar
  5. Z. A. Andrade, S. G. Andrade, R. Correa, M. Sadigursky, and V. J. Ferrans, “Myocardial changes in acute Trypanosoma cruzi infection. Ultrastructural evidence of immune damage and the role of microangiopathy,” The American Journal of Pathology, vol. 144, no. 6, pp. 1403–1411, 1994. View at: Google Scholar
  6. A. Rassi Jr., A. Rassi, and W. C. Little, “Chagas' heart disease,” Clinical Cardiology, vol. 23, no. 12, pp. 883–889, 2000. View at: Publisher Site | Google Scholar
  7. M. de Lourdes Higuchi, L. A. Benvenuti, M. M. Reis, and M. Metzger, “Pathophysiology of the heart in Chagas' disease: current status and new developments,” Cardiovascular Research, vol. 60, no. 1, pp. 96–107, 2003. View at: Publisher Site | Google Scholar
  8. M. B. P. Scares, L. Pontes-De-Carvalho, and R. Ribeiro-Dos-Santos, “The pathogenesis of Chagas' disease: when autoimmune and parasite-specific immune responses meet,” Anais da Academia Brasileira de Ciências, vol. 73, no. 4, pp. 547–559, 2001. View at: Publisher Site | Google Scholar
  9. F. Kierszenbaum, “Mechanisms of pathogenesis in Chagas disease,” Acta Parasitologica, vol. 52, no. 1, pp. 1–12, 2007. View at: Publisher Site | Google Scholar
  10. J. F. Turrens, “Mitochondrial formation of reactive oxygen species,” The Journal of Physiology, vol. 552, no. 2, pp. 335–344, 2003. View at: Publisher Site | Google Scholar
  11. P. J. Andrew and B. Mayer, “Enzymatic function of nitric oxide synthases,” Cardiovascular Research, vol. 43, no. 3, pp. 521–531, 1999. View at: Publisher Site | Google Scholar
  12. M. N. Alvarez, L. Piacenza, F. Irigoín, G. Peluffo, and R. Radi, “Macrophage-derived peroxynitrite diffusion and toxicity to Trypanosoma cruzi,” Archives of Biochemistry and Biophysics, vol. 432, no. 2, pp. 222–232, 2004. View at: Publisher Site | Google Scholar
  13. M. A. Muñoz-Fernández, M. A. Fernández, and M. Fresno, “Activation of human macrophages for the killing of intracellular Trypanosoma cruzi by TNF-α and IFN-γ through a nitric oxide-dependent mechanism,” Immunology Letters, vol. 33, no. 1, pp. 35–40, 1992. View at: Publisher Site | Google Scholar
  14. R. C. Melo, D. L. Fabrino, H. D'Avila, H. C. Teixeira, and A. P. Ferreira, “Production of hydrogen peroxide by peripheral blood monocytes and specific macrophages during experimental infection with Trypanosoma cruzi in vivo,” Cell Biology International, vol. 27, no. 10, pp. 853–861, 2003. View at: Publisher Site | Google Scholar
  15. G. A. Martins, M. A. G. Cardoso, J. C. S. Aliberti, and J. S. Silva, “Nitric oxide-induced apoptotic cell death in the acute phase of Trypanosoma cruzi infection in mice,” Immunology Letters, vol. 63, no. 2, pp. 113–120, 1998. View at: Publisher Site | Google Scholar
  16. M. Bergeron and M. Olivier, “Trypanosoma cruzi-mediated IFN-γ-inducible nitric oxide output in macrophages is regulated by iNOS mRNA stability,” The Journal of Immunology, vol. 177, no. 9, pp. 6271–6280, 2006. View at: Google Scholar
  17. M. Dhiman, J. G. Estrada-Franco, J. M. Pando et al., “Increased myeloperoxidase activity and protein nitration are indicators of inflammation in patients with Chagas' disease,” Clinical and Vaccine Immunology, vol. 16, no. 5, pp. 660–666, 2009. View at: Publisher Site | Google Scholar
  18. R. Pérez-Fuentes, J.-F. Guégan, C. Barnabé et al., “Severity of chronic Chagas disease is associated with cytokine/antioxidant imbalance in chronically individuals,” International Journal for Parasitology, vol. 33, no. 3, pp. 293–299, 2003. View at: Publisher Site | Google Scholar
  19. R. Pérez-Fuentes, M. D. C. Sánchez-Guillén, C. González-Alvarez, V. M. Monteón, P. A. Reyes, and J. L. Rosales-Encina, “Humoral nitric oxide levels and antibody immune response of symptomatic and indeterminate Chagas' disease patients to commercial and autochthonous Trypanosoma cruzi antigen,” The American Journal of Tropical Medicine and Hygiene, vol. 58, no. 6, pp. 715–720, 1998. View at: Google Scholar
  20. H. A. Carrasco Guerra, E. Palacios-Prü, C. Dagert de Scorza, C. Molina, G. Inglessis, and R. V. Mendoza, “Clinical, histochemical, and ultrastructural correlation in septal endomyocardial biopsies from chronic chagasic patients: detection of early myocardial damage,” American Heart Journal, vol. 113, no. 3, pp. 716–724, 1987. View at: Publisher Site | Google Scholar
  21. E. Palacios-Pru, H. Carrasco, C. Scorza, and R. Espinoza, “Ultrastructural characteristics of different stages of human chagasic myocarditis,” The American Journal of Tropical Medicine and Hygiene, vol. 41, no. 1, pp. 29–40, 1989. View at: Google Scholar
  22. H. Parada, H. A Carrasco, N. Añez, C. Fuenmayor, and I. Inglessis, “Cardiac involvement is a constant finding in acute Chagas' disease: a clinical, parasitological and histopathological study,” International Journal of Cardiology, vol. 60, no. 1, pp. 49–54, 1997. View at: Publisher Site | Google Scholar
  23. N. Garg, V. L. Popov, and J. Papaconstantinou, “Profiling gene transcription reveals a deficiency of mitochondrial oxidative phosphorylation in Trypanosoma cruzi-infected murine hearts: implications in chagasic myocarditis development,” Biochimica et Biophysica Acta, vol. 1638, no. 2, pp. 106–120, 2003. View at: Google Scholar
  24. E. Cunha-Neto, V. J. Dzau, P. D. Allen et al., “Cardiac gene expression profiling provides evidence for cytokinopathy as a molecular mechanism in Chagas' disease cardiomyopathy,” American Journal of Pathology, vol. 167, no. 2, pp. 305–313, 2005. View at: Google Scholar
  25. S. Mukherjee, T. J. Belbin, D. C. Spray et al., “Microarray analysis of changes in gene expression in a murine model of chronic chagasic cardiomyopathy,” Parasitology Research, vol. 91, no. 3, pp. 187–196, 2003. View at: Publisher Site | Google Scholar
  26. N. Garg, A. Gerstner, V. Bhatia, J. DeFord, and J. Papaconstantinou, “Gene expression analysis in mitochondria from chagasic mice: alterations in specific metabolic pathways,” Biochemical Journal, vol. 381, no. 3, pp. 743–752, 2004. View at: Publisher Site | Google Scholar
  27. G. Vyatkina, V. Bhatia, A. Gerstner, J. Papaconstantinou, and N. Garg, “Impaired mitochondrial respiratory chain and bioenergetics during chagasic cardiomyopathy development,” Biochimica et Biophysica Acta, vol. 1689, no. 2, pp. 162–173, 2004. View at: Publisher Site | Google Scholar
  28. S. A. Uyemura, M. C. Jordani, A. C. M. Polizello, and C. Curti, “Heart FoF1-ATPase changes during the acute phase of Trypanosoma cruzi infection in rats,” Molecular and Cellular Biochemistry, vol. 165, no. 2, pp. 127–133, 1996. View at: Publisher Site | Google Scholar
  29. S. A. Uyemura, S. Albuquerque, and C. Curti, “Energetics of heart mitochondria during acute phase of Trypanosoma cruzi infection in rats,” The International Journal of Biochemistry & Cell Biology, vol. 27, no. 11, pp. 1183–1189, 1995. View at: Publisher Site | Google Scholar
  30. J.-J. Wen, V. Bhatia, V. L. Popov, and N. J. Garg, “Phenyl-α-tert-butyl nitrone reverses mitochondrial decay in acute Chagas' disease,” American Journal of Pathology, vol. 169, no. 6, pp. 1953–1964, 2006. View at: Publisher Site | Google Scholar
  31. A. Boveris, N. Oshino, and B. Chance, “The cellular production of hydrogen peroxide,” Biochemical Journal, vol. 128, no. 3, pp. 617–630, 1972. View at: Google Scholar
  32. T. Ide, H. Tsutsui, S. Kinugawa et al., “Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium,” Circulation Research, vol. 85, no. 4, pp. 357–363, 1999. View at: Google Scholar
  33. Q. Chen, E. J. Vazquez, S. Moghaddas, C. L. Hoppel, and E. J. Lesnefsky, “Production of reactive oxygen species by mitochondria: central role of complex III,” The Journal of Biological Chemistry, vol. 278, no. 38, pp. 36027–36031, 2003. View at: Publisher Site | Google Scholar
  34. J. J. Wen and N. J. Garg, “Mitochondrial generation of reactive oxygen species is enhanced at the Qo site of the complex III in the myocardium of Trypanosoma cruzi-infected mice: beneficial effects of an antioxidant,” Journal of Bioenergetics and Biomembranes, vol. 40, no. 6, pp. 587–598, 2008. View at: Publisher Site | Google Scholar
  35. I. Fridovich, “Superoxide radical and superoxide dismutases,” Annual Review of Biochemistry, vol. 64, pp. 97–112, 1995. View at: Publisher Site | Google Scholar
  36. I. Fridovich, “Superoxide dismutases,” in Advances in Enzymology and Related Areas of Molecular Biology, Vol. 41, pp. 35–97, John Wiley & Sons, New York, NY, USA, 1974. View at: Publisher Site | Google Scholar
  37. J. Nordberg and E. S. J. Arnér, “Reactive oxygen species, antioxidants, and the mammalian thioredoxin system,” Free Radical Biology and Medicine, vol. 31, no. 11, pp. 1287–1312, 2001. View at: Publisher Site | Google Scholar
  38. H. Z. Chae, S. W. Kang, and S. G. Rhee, “Isoforms of mammalian peroxiredoxin that reduce peroxides in presence of thioredoxin,” Methods in Enzymology, vol. 300, pp. 219–226, 1999. View at: Publisher Site | Google Scholar
  39. N. S. Dhalla, A. B. Elmoselhi, T. Hata, and N. Makino, “Status of myocardial antioxidants in ischemia-reperfusion injury,” Cardiovascular Research, vol. 47, no. 3, pp. 446–456, 2000. View at: Publisher Site | Google Scholar
  40. N. Marczin, N. El-Habashi, G. S. Hoare, R. E. Bundy, and M. Yacoub, “Antioxidants in myocardial ischemia-reperfusion injury: therapeutic potential and basic mechanisms,” Archives of Biochemistry and Biophysics, vol. 420, no. 2, pp. 222–236, 2003. View at: Publisher Site | Google Scholar
  41. J.-J. Wen and N. Garg, “Oxidative modification of mitochondrial respiratory complexes in response to the stress of Trypanosoma cruzi infection,” Free Radical Biology and Medicine, vol. 37, no. 12, pp. 2072–2081, 2004. View at: Publisher Site | Google Scholar
  42. J.-J. Wen, P. C. Yachelini, A. Sembaj, R. E. Manzur, and N. J. Garg, “Increased oxidative stress is correlated with mitochondrial dysfunction in chagasic patients,” Free Radical Biology and Medicine, vol. 41, no. 2, pp. 270–276, 2006. View at: Publisher Site | Google Scholar
  43. T. B. de Oliveira, R. C. Pedrosa, and D. W. Filho, “Oxidative stress in chronic cardiopathy associated with Chagas disease,” International Journal of Cardiology, vol. 116, no. 3, pp. 357–363, 2007. View at: Publisher Site | Google Scholar
  44. T. Finkel, “Oxidant signals and oxidative stress,” Currnet Opinion in Cell Biology, vol. 15, no. 2, pp. 247–254, 2003. View at: Publisher Site | Google Scholar
  45. W. Dröge, “Free radicals in the physiological control of cell function,” Physiological Reviews, vol. 82, no. 1, pp. 47–95, 2002. View at: Google Scholar
  46. A. Valenzuela, “The biological significance of malondialdehyde determination in the assessment of tissue oxidative stress,” Life Sciences, vol. 48, no. 4, pp. 301–309, 1991. View at: Publisher Site | Google Scholar
  47. H. Ohkawa, N. Ohishi, and K. Yagi, “Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction,” Analytical Biochemistry, vol. 95, no. 2, pp. 351–358, 1979. View at: Publisher Site | Google Scholar
  48. N. Zarkovic, “4-hydroxynonenal as a bioactive marker of pathophysiological processes,” Molecular Aspects of Medicine, vol. 24, no. 4-5, pp. 281–291, 2003. View at: Publisher Site | Google Scholar
  49. K. Uchida and E. R. Stadtman, “Modification of histidine residues in proteins by reaction with 4-hydroxynonenal,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 10, pp. 4544–4548, 1992. View at: Publisher Site | Google Scholar
  50. D. A. Butterfield, T. Koppal, B. Howard et al., “Structural and functional changes in proteins induced by free radical-mediated oxidative stress and protective action of the antioxidants N-tert-butyl-a-phenylnitrone and vitamin E,” Annals of the New York Academy of Sciences, vol. 854, pp. 448–462, 1998. View at: Publisher Site | Google Scholar
  51. M. Chevion, E. Berenshtein, and E. R. Stadtman, “Human studies related to protein oxidation: protein carbonyl content as a marker of damage,” Free Radical Research, vol. 33, supplement, pp. S99–S108, 2000. View at: Google Scholar
  52. F. J. Schopfer, P. R. S. Baker, and B. A. Freeman, “NO-dependent protein nitration: a cell signaling event or an oxidative inflammatory response?” Trends in Biochemical Sciences, vol. 28, no. 12, pp. 646–654, 2003. View at: Publisher Site | Google Scholar
  53. R. A. Floyd, M. West, and K. Hensley, “Oxidative biochemical markers; clues to understanding aging in long-lived species,” Experimental Gerontology, vol. 36, no. 4–6, pp. 619–640, 2001. View at: Publisher Site | Google Scholar
  54. M. D. Evans and M. S. Cooke, “Factors contributing to the outcome of oxidative damage to nucleic acids,” BioEssays, vol. 26, no. 5, pp. 533–542, 2004. View at: Publisher Site | Google Scholar
  55. A. B. Younés-Chennoufi, M. Hontebeyrie-Joskowicz, V. Tricottet, H. Eisen, M. Reynes, and G. Said, “Persistence of Trypanosoma cruzi antigens in the inflammatory lesions of chronically infected mice,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 82, no. 1, pp. 77–83, 1988. View at: Publisher Site | Google Scholar
  56. R. L. Cardoni, M. I. Antunez, C. Morales, and I. Rodriguez Nantes, “Release of reactive oxygen species by phagocytic cells in response to live parasites in mice infected with Trypanosoma cruzi,” The American Journal of Tropical Medicine and Hygiene, vol. 56, no. 3, pp. 329–334, 1997. View at: Google Scholar
  57. F. Villalta and F. Kierszenbaum, “Role of polymorphonuclear cells in Chagas' disease. I. Uptake and mechanisms of destruction of intracellular (amastigote) forms of Trypanosoma cruzi by human neutrophils,” The Journal of Immunology, vol. 131, no. 3, pp. 1504–1510, 1983. View at: Google Scholar
  58. J.-J. Wen, M. Dhiman, E. B. Whorton, and N. J. Garg, “Tissue-specific oxidative imbalance and mitochondrial dysfunction during Trypanosoma cruzi infection in mice,” Microbes and Infection, vol. 10, no. 10-11, pp. 1201–1209, 2008. View at: Publisher Site | Google Scholar
  59. B. Chance, H. Sies, and A. Boveris, “Hydroperoxide metabolism in mammalian organs,” Physiological Reviews, vol. 59, no. 3, pp. 527–605, 1979. View at: Google Scholar
  60. A. Boveris, E. Cadenas, and A. O. M. Stoppani, “Role of ubiquinone in the mitochondrial generation of hydrogen peroxide,” Biochemical Journal, vol. 156, no. 2, pp. 435–444, 1976. View at: Google Scholar
  61. J. F. Turrens, “The potential of antioxidant enzymes as pharmacological agents in vivo,” Xenobiotica, vol. 21, no. 8, pp. 1033–1040, 1991. View at: Google Scholar
  62. K. Carvajal and R. Moreno-Sánchez, “Heart metabolic disturbances in cardiovascular diseases,” Archives of Medical Research, vol. 34, no. 2, pp. 89–99, 2003. View at: Publisher Site | Google Scholar
  63. D. Han, R. Canali, D. Rettori, and N. Kaplowitz, “Effect of gutathione depletion on sites and topology of superoxide and hydrogen peroxide production in mitochondria,” Molecular Pharmacology, vol. 64, no. 5, pp. 1136–1144, 2003. View at: Publisher Site | Google Scholar
  64. B. Halliwell and J. M. C. Gutteridge, “Oxygen toxicity, oxygen radicals, transition metals and disease,” Biochemical Journal, vol. 219, no. 1, pp. 1–14, 1984. View at: Google Scholar
  65. L. Y. Brovko, N. A. Romanova, and N. N. Ugarova, “Bioluminescent assay of bacterial intracellular AMP, ADP, and ATP with the use of a coimmobilized three-enzyme reagent (adenylate kinase, pyruvate kinase, and firefly luciferase),” Analytical Biochemistry, vol. 220, no. 2, pp. 410–414, 1994. View at: Publisher Site | Google Scholar
  66. J. D. Rush and W. H. Koppenol, “Oxidizing intermediates in the reaction of ferrous EDTA with hydrogen peroxide. Reactions with organic molecules and ferrocytochrome C,” The Journal of Biological Chemistry, vol. 261, no. 15, pp. 6730–6733, 1986. View at: Google Scholar
  67. D. A. Dickinson and H. J. Forman, “Glutathione in defense and signaling: lessons from a small thiol,” Annals of the New York Academy of Sciences, vol. 973, pp. 488–504, 2002. View at: Google Scholar
  68. J. Wang, H. Chen, T. Wang, Y. Diao, and K. Tian, “Oxygen-derived free radicals induced cellular injury in superior mesenteric artery occlusion shock: protective effect of superoxide dismutase,” Circulatory Shock, vol. 32, no. 1, pp. 31–41, 1990. View at: Google Scholar
  69. S. Cuzzocrea, G. Costantino, E. Mazzon, A. De Sarro, and A. P. Caputi, “Beneficial effects of Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), a superoxide dismutase mimetic, in zymosan-induced shock,” British Journal of Pharmacology, vol. 128, no. 6, pp. 1241–1251, 1999. View at: Publisher Site | Google Scholar
  70. D. Salvemini, Z.-Q. Wang, J. L. Zweier et al., “A nonpeptidyl mimic of superoxide dismutase with therapeutic activity in rats,” Science, vol. 286, no. 5438, pp. 304–306, 1999. View at: Publisher Site | Google Scholar
  71. R. A. Floyd, K. Hensley, M. J. Forster, J. A. Kelleher-Anderson, and P. L. Wood, “Nitrones as neuroprotectants and antiaging drugs,” Annals of the New York Academy of Sciences, vol. 959, pp. 321–329, 2002. View at: Google Scholar
  72. Y. Kotake, “Pharmacologic properties of phenyl N-tert-butylnitrone,” Antioxidants & Redox Signaling, vol. 1, no. 4, pp. 481–499, 1999. View at: Publisher Site | Google Scholar
  73. L. B. Maçao, D. W. Filho, R. C. Pedrosa et al., “Antioxidant therapy attenuates oxidative stress in chronic cardiopathy associated with Chagas' disease,” International Journal of Cardiology, vol. 123, no. 1, pp. 43–49, 2007. View at: Publisher Site | Google Scholar
  74. J. S. M. Oliveira, “A natural human model of intrinsic heart nervous system denervation: Chagas' cardiopathy,” American Heart Journal, vol. 110, no. 5, pp. 1092–1098, 1985. View at: Publisher Site | Google Scholar
  75. J. A. Marin-Neto, M. V. Simões, E. M. Ayres-Neto et al., “Studies of the coronary circulation in Chagas' heart disease,” São Paulo Medical Journal, vol. 113, no. 2, pp. 826–834, 1995. View at: Google Scholar
  76. H. Acquatella and N. B. Schiller, “Echocardiographic recognition of Chagas' disease and endomyocardial fibrosis,” Journal of the American Society of Echocardiography, vol. 1, no. 1, pp. 60–68, 1988. View at: Google Scholar
  77. M. A. Rossi, “Microvascular changes as a cause of chronic cardiomyopathy in Chagas' disease,” American Heart Journal, vol. 120, no. 1, pp. 233–236, 1990. View at: Publisher Site | Google Scholar
  78. M. A. Rossi, “Aortic endothelial cell changes in the acute septicemic phase of experimental Trypanosoma cruzi infection in rats: scanning and transmission electron microscopic study,” The American Journal of Tropical Medicine and Hygiene, vol. 57, no. 3, pp. 321–327, 1997. View at: Google Scholar
  79. H. B. Tanowitz, D. K. Kaul, B. Chen et al., “Compromised microcirculation in acute murine Trypanosoma cruzi infection,” Journal of Parasitology, vol. 82, no. 1, pp. 124–130, 1996. View at: Publisher Site | Google Scholar
  80. S. G. Ramos and M. A. Rossi, “Microcirculation and Chagas' disease: hypothesis and recent results,” Revista do Instituto de Medicina Tropical de Sao Paulo, vol. 41, no. 2, pp. 123–129, 1999. View at: Publisher Site | Google Scholar
  81. H. M. Piper, T. Noll, and B. Siegmund, “Mitochondrial function in the oxygen depleted and reoxygenated myocardial cell,” Cardiovascular Research, vol. 28, no. 1, pp. 1–15, 1994. View at: Publisher Site | Google Scholar
  82. V. Borutaite, R. Morkuniene, A. Budriunaite et al., “Kinetic analysis of changes in activity of heart mitochondrial oxidative phosphorylation system induced by ischemia,” Journal of Molecular and Cellular Cardiology, vol. 28, no. 10, pp. 2195–2201, 1996. View at: Publisher Site | Google Scholar
  83. R. B. Jennings and C. E. Ganote, “Mitochondrial structure and function in acute myocardial ischemic injury,” Circulation Research, vol. 38, no. 5, supplement 1, pp. 80–91, 1976. View at: Google Scholar
  84. K. Ataka, D. Chen, S. Levitsky, E. Jimenez, and H. Feinberg, “Effect of aging on intracellular Ca2+, pHi, and contractility during ischemia and reperfusion,” Circulation, vol. 86, no. 5, supplement 2, pp. 371–376, 1992. View at: Google Scholar
  85. V. Borutaite and G. C. Brown, “Mitochondria in apoptosis of ischemic heart,” FEBS Letters, vol. 541, no. 3, pp. 1–5, 2003. View at: Publisher Site | Google Scholar
  86. M. Shlafer, C. L. Myers, and S. Adkins, “Mitochondrial hydrogen peroxide generation and activities of glutathione peroxidase and superoxide dismutase following global ischemia,” Journal of Molecular and Cellular Cardiology, vol. 19, no. 12, pp. 1195–1206, 1987. View at: Publisher Site | Google Scholar
  87. E. J. Lesnefsky, S. Moghaddas, B. Tandler, J. Kerner, and C. L. Hoppel, “Mitochondrial dysfunction in cardiac disease: ischemia-reperfusion, aging, and heart failure,” Journal of Molecular and Cellular Cardiology, vol. 33, no. 6, pp. 1065–1089, 2001. View at: Publisher Site | Google Scholar
  88. R. A. Simonyan and V. P. Skulachev, “Thermoregulatory uncoupling in heart muscle mitochondria: involvement of the ATP/ADP antiporter and uncoupling protein,” FEBS Letters, vol. 436, no. 1, pp. 81–84, 1998. View at: Publisher Site | Google Scholar
  89. S. S. Korshunov, B. F. Krasnikov, M. O. Pereverzev, and V. P. Skulachev, “The antioxidant functions of cytochrome c,” FEBS Letters, vol. 462, no. 1, pp. 192–198, 1999. View at: Publisher Site | Google Scholar

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