Cardiomyocyte diffusible redox mediators control<i>Trypanosoma cruzi</i>infection: role of parasite mitochondrial iron superoxide dismutase

Estrada, Damián; Specker, Gabriela; Martínez, Alejandra; Dias, Patrícia Pereira; Hissa, Bárbara; Andrade, Luciana O.; Radí, Rafael; Piacenza, Lucı́a

doi:10.1042/bcj20170698

Cited by 27 publications

(31 citation statements)

References 51 publications

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“…These findings demonstrate that unbalanced NO levels worsens the outcome of experimental CD, suggesting that not only the amount of ROS/NO but the stoichiometry between them might be determinant to the outcome of CD prognosis. With that in mind, here we provide evidence that NOX2-derived ROS is important to balance NO overproduction during T. cruzi infection, and that inhibition of NOX2, alone, worsens the cardiac outcome, even though other studies have demonstrated that controlling ROS production through NOX2 [74] or through NOX in general [32] controls T. cruzi-induced infection and ameliorates myocarditis. Treatment with non-specific antioxidants were shown to be effective to prevent [17] or to revert [18] experimental CD.…”

Section: Plos Pathogensmentioning

confidence: 62%

Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease

et al. 2020

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Chagas Disease (CD) is one of the leading causes of heart failure and sudden death in Latin America. Treatments with antioxidants have provided promising alternatives to ameliorate CD. However, the specific roles of major reactive oxygen species (ROS) sources, including NADPH-oxidase 2 (NOX2), mitochondrial-derived ROS and nitric oxide (NO) in the progression or resolution of CD are yet to be elucidated. We used C57BL/6 (WT) and a gp91 PHOX knockout mice (PHOX-/-), lacking functional NOX2, to investigate the effects of ablation of NOX2-derived ROS production on the outcome of acute chagasic cardiomyopathy. Infected PHOX-/cardiomyocytes displayed an overall pro-arrhythmic phenotype, notably with higher arrhythmia incidence on ECG that was followed by higher number of early afterdepolarizations (EAD) and 2.5-fold increase in action potential (AP) duration alternans, compared to AP from infected WT mice. Furthermore, infected PHOX-/cardiomyocytes display increased diastolic [Ca 2+ ], aberrant Ca 2+ transient and reduced Ca 2+ transient amplitude. Cardiomyocyte contraction is reduced in infected WT and PHOX-/mice, to a similar extent. Nevertheless, only infected PHOX-/isolated cardiomyocytes displayed significant increase in non-triggered extra contractions (appearing in~75% of cells). Electro-mechanical remodeling of infected PHOX-/cardiomyocytes is associated with increase in NO and mitochondria-derived ROS production. Notably, EADs, AP duration alternans and in vivo arrhythmias were reverted by pre-incubation with nitric oxide synthase inhibitor L-NAME. Overall our data show for the first time that lack of NOX2-derived ROS promoted a pro-arrhythmic phenotype in the heart, in which the crosstalk between ROS and NO could play an important role in regulating cardiomyocyte electro-mechanical function during acute CD. Future studies designed to evaluate the potential role of NOX2-derived ROS in the chronic phase of CD could open new and more specific therapeutic strategies to treat CD and prevent deaths due to heart complications.

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Section: Plos Pathogensmentioning

confidence: 62%

Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease

et al. 2020

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“… Manque et al (2011) found that the most up-regulated pathways in the early infection were related to a inflammatory response, whereas mitochondrial energetic related genes did not change significantly. Also by using murine cardiomyocytes a decrease in oxidative phosphorylation was reported ( Vyatkina et al, 2004 ; Estrada et al, 2018 ). However, our results are in agreement with gene profiling studies on human heart biopsies.…”

Section: Discussionmentioning

confidence: 98%

Early Trypanosoma cruzi Infection Triggers mTORC1-Mediated Respiration Increase and Mitochondrial Biogenesis in Human Primary Cardiomyocytes

et al. 2018

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Chagasic chronic cardiomyopathy is one of the most frequent and severe manifestations of Chagas disease, caused by the parasite Trypanosoma cruzi. The pathogenic and biochemical mechanisms responsible for cardiac lesions remain not completely understood, although it is clear that hypertrophy and subsequent heart dilatation is in part caused by the direct infection of cardiomyocytes. In this work, we evaluated the initial response of human cardiomyocytes to T. cruzi infection by transcriptomic profiling. Immediately after infection, cardiomyocytes dramatically change their gene expression patterns, up regulating most of the genes encoding for respiratory chain, oxidative phosphorylation and protein synthesis. We found that these changes correlate with an increase in basal and maximal respiration, as well as in spare respiratory capacity, which is accompanied by mitochondrial biogenesis pgc-1α independent. We also demonstrate that these changes are mediated by mTORC1 and reversed by rapamycin, resembling the molecular mechanisms described for the non-chagasic hypertrophic cardiomyopathy. The results of the present work identify that early during infection, the activation of mTORC1, mitochondrial biogenesis and improvement in oxidative phosphorylation are key biochemical changes that provide new insights into the host response to parasite infection and the pathogenesis of chronic chagasic cardiomyopathy. The finding that this phenotype can be reversed opens a new perspective in the treatment of Chagas disease, through the identification of host targets, and the use of combined parasite and host targeted therapies, in order to prevent chagasic cardiomyopathy.

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“…•− detoxification and the fine-tuning of the death-signaling process (12,51). The interplay of Fe-SODB with cytosolic O 2…”

Section: •−mentioning

confidence: 99%

Cytosolic Fe-superoxide dismutase safeguardsTrypanosoma cruzifrom macrophage-derived superoxide radical

Martínez

Prolo

Estrada

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Trypanosoma cruzi, the causative agent of Chagas disease (CD), contains exclusively Fe-dependent superoxide dismutases (Fe-SODs). During T. cruzi invasion to macrophages, superoxide radical (O2•−) is produced at the phagosomal compartment toward the internalized parasite via NOX-2 (gp91-phox) activation. In this work, T. cruzi cytosolic Fe-SODB overexpressers (pRIBOTEX–Fe-SODB) exhibited higher resistance to macrophage-dependent killing and enhanced intracellular proliferation compared with wild-type (WT) parasites. The higher infectivity of Fe-SODB overexpressers compared with WT parasites was lost in gp91-phox−/− macrophages, underscoring the role of O2•− in parasite killing. Herein, we studied the entrance of O2•− and its protonated form, perhydroxyl radical [(HO2•); pKa = 4.8], to T. cruzi at the phagosome compartment. At the acidic pH values of the phagosome lumen (pH 5.3 ± 0.1), high steady-state concentrations of O2•− and HO2• were estimated (∼28 and 8 µM, respectively). Phagosomal acidification was crucial for O2•− permeation, because inhibition of the macrophage H+-ATPase proton pump significantly decreased O2•− detection in the internalized parasite. Importantly, O2•− detection, aconitase inactivation, and peroxynitrite generation were lower in Fe-SODB than in WT parasites exposed to external fluxes of O2•− or during macrophage infections. Other mechanisms of O2•− entrance participate at neutral pH values, because the anion channel inhibitor 5-nitro-2-(3-phenylpropylamino) benzoic acid decreased O2•− detection. Finally, parasitemia and tissue parasite burden in mice were higher in Fe-SODB–overexpressing parasites, supporting the role of the cytosolic O2•−-catabolizing enzyme as a virulence factor for CD.

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Cardiomyocyte diffusible redox mediators controlTrypanosoma cruziinfection: role of parasite mitochondrial iron superoxide dismutase

Cited by 27 publications

References 51 publications

Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease

Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease

Early Trypanosoma cruzi Infection Triggers mTORC1-Mediated Respiration Increase and Mitochondrial Biogenesis in Human Primary Cardiomyocytes

Cytosolic Fe-superoxide dismutase safeguardsTrypanosoma cruzifrom macrophage-derived superoxide radical

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