Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease.
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), mitoc...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-03-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1008379 |
| _version_ | 1818348695973789696 |
|---|---|
| author | Artur Santos-Miranda Julliane Vasconcelos Joviano-Santos Grazielle Alves Ribeiro Ana Flávia M Botelho Peter Rocha Leda Quercia Vieira Jader Santos Cruz Danilo Roman-Campos |
| author_facet | Artur Santos-Miranda Julliane Vasconcelos Joviano-Santos Grazielle Alves Ribeiro Ana Flávia M Botelho Peter Rocha Leda Quercia Vieira Jader Santos Cruz Danilo Roman-Campos |
| author_sort | Artur Santos-Miranda |
| collection | DOAJ |
| description | 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 gp91PHOX 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 [Ca2+], aberrant Ca2+ transient and reduced Ca2+ 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. |
| first_indexed | 2024-12-13T17:54:09Z |
| format | Article |
| id | doaj.art-25bd5ba0e3994771bdb26dcca2e7f118 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-13T17:54:09Z |
| publishDate | 2020-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-25bd5ba0e3994771bdb26dcca2e7f1182022-12-21T23:36:25ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742020-03-01163e100837910.1371/journal.ppat.1008379Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease.Artur Santos-MirandaJulliane Vasconcelos Joviano-SantosGrazielle Alves RibeiroAna Flávia M BotelhoPeter RochaLeda Quercia VieiraJader Santos CruzDanilo Roman-CamposChagas 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 gp91PHOX 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 [Ca2+], aberrant Ca2+ transient and reduced Ca2+ 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.https://doi.org/10.1371/journal.ppat.1008379 |
| spellingShingle | Artur Santos-Miranda Julliane Vasconcelos Joviano-Santos Grazielle Alves Ribeiro Ana Flávia M Botelho Peter Rocha Leda Quercia Vieira Jader Santos Cruz Danilo Roman-Campos Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease. PLoS Pathogens |
| title | Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease. |
| title_full | Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease. |
| title_fullStr | Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease. |
| title_full_unstemmed | Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease. |
| title_short | Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease. |
| title_sort | reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental chagas disease |
| url | https://doi.org/10.1371/journal.ppat.1008379 |
| work_keys_str_mv | AT artursantosmiranda reactiveoxygenspeciesandnitricoxideimbalancesleadtoinvivoandinvitroarrhythmogenicphenotypeinacutephaseofexperimentalchagasdisease AT jullianevasconcelosjovianosantos reactiveoxygenspeciesandnitricoxideimbalancesleadtoinvivoandinvitroarrhythmogenicphenotypeinacutephaseofexperimentalchagasdisease AT graziellealvesribeiro reactiveoxygenspeciesandnitricoxideimbalancesleadtoinvivoandinvitroarrhythmogenicphenotypeinacutephaseofexperimentalchagasdisease AT anaflaviambotelho reactiveoxygenspeciesandnitricoxideimbalancesleadtoinvivoandinvitroarrhythmogenicphenotypeinacutephaseofexperimentalchagasdisease AT peterrocha reactiveoxygenspeciesandnitricoxideimbalancesleadtoinvivoandinvitroarrhythmogenicphenotypeinacutephaseofexperimentalchagasdisease AT ledaquerciavieira reactiveoxygenspeciesandnitricoxideimbalancesleadtoinvivoandinvitroarrhythmogenicphenotypeinacutephaseofexperimentalchagasdisease AT jadersantoscruz reactiveoxygenspeciesandnitricoxideimbalancesleadtoinvivoandinvitroarrhythmogenicphenotypeinacutephaseofexperimentalchagasdisease AT daniloromancampos reactiveoxygenspeciesandnitricoxideimbalancesleadtoinvivoandinvitroarrhythmogenicphenotypeinacutephaseofexperimentalchagasdisease |