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[This corrects the article DOI: 10.1371/journal.ppat.1008379.].
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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 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.
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Arritmias Cardíacas/metabolismo , Señalización del Calcio , Cardiomiopatía Chagásica/metabolismo , Miocitos Cardíacos/metabolismo , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Enfermedad Aguda , Animales , Arritmias Cardíacas/genética , Arritmias Cardíacas/patología , Arritmias Cardíacas/fisiopatología , Calcio/metabolismo , Cardiomiopatía Chagásica/genética , Cardiomiopatía Chagásica/patología , Cardiomiopatía Chagásica/fisiopatología , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Noqueados , Miocitos Cardíacos/patología , NADPH Oxidasa 2/genética , NADPH Oxidasa 2/metabolismoRESUMEN
In the present study, we investigated the cardioprotective effects of coenzyme Q10 (Q10) against doxorubicin (DOXO) induced cardiomyopathy. Twenty adult rats were distributed in four experimental groups: group 1 received NaCl 0.9% at 1 ml/day for 14 days; group 2 received Q10 at 1 mg/kg/day for 14 days; group 3 received initial 7 days of treatment with NaCl 0.9% followed by a single dose of doxorubicin (12.5 mg/kg IP) and another 7 days of NaCl; and group 4 received initial 7 days of Q10 1 mg/kg/day, followed by a single dose of doxorubicin (12.5 mg/kg IP) and another 7 days of Q10. At the end of 14 days, systolic, diastolic and mean blood pressure, electrocardiogram (ECG), complete blood count, and serum biochemical profile were evaluated. We also analyzed heart histological and ultrastructure analysis, and estimated heart's oxidative stress and lipid peroxidation. DOXO administration altered ECG, with increase heart rate, P-wave duration, PR interval duration, and T-wave amplitude. All the parameters were significantly reduced following Q10 treatment. DOXO also caused increase in CK, CK-MB, LDH, and urea levels, which were not mitigated by Q10 treatment. However, Q10 reduced oxidative stress by interfering with superoxide dismutase, significantly decreasing lipid peroxidation in heart tissue. DOXO administration also leads to several histological and ultrastructure alterations including cardiomyocyte degeneration and intense intracelullar autophagosomes, all minimized by Q10 treatment. Q10 treatment prevented the ECG changes, minimized oxidative stress, lipid peroxidation, and DOXO-induced heart tissue alterations. Our findings suggest that pre- and post-treatment with Q10 exerts potential cardioprotective effect against the DOX-induced cardiotoxicity.
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Antioxidantes/farmacología , Cardiomiopatías/prevención & control , Doxorrubicina , Miocitos Cardíacos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ubiquinona/análogos & derivados , Animales , Cardiomiopatías/inducido químicamente , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Cardiotoxicidad , Modelos Animales de Enfermedad , Peroxidación de Lípido/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/ultraestructura , Ratas Wistar , Ubiquinona/farmacologíaRESUMEN
Cardiac glycosides (CGs) are secondary compounds found in plants and amphibians and are widely distributed in nature with potential cardiovascular action. Their mechanism is based on the blockage of the heart's sodium potassium ATPase, with a positive inotropic effect. Some of the most well-known CGs are digoxin, ouabain, oleandrin, and bufalin. They have similar chemical structures: a lactone ring, steroid ring, and sugar moiety. Digoxin, ouabain, and oleandrin are classified as cardenolides, consisting of a lactone ring with five carbons, while bufalin is classified as bufodienolides, with a six-carbon ring. Small structural differences determine variations in the toxicokinetics and toxicodynamics of such substances. Most case reports of poisoning caused by CGs are associated with cardiovascular toxicity, causing a variety of arrhythmias and lesions in the heart tissue. Experimental studies also describe important similarities among different CGs, especially regarding species sensitivity. Recent studies furthermore focus on their antineoplastic potential, with controversial results. Data from research studies and case reports were reviewed to identify the main characteristics of the CGs, including toxicokinetics, toxicodynamics, clinical signs, electrocardiographic, pathological findings, antineoplastic potential and the main techniques used for diagnostic purposes.