RESUMEN
Non-pharmacological strategies have been rarely described in the treatment of infectious diseases. Although exercise training has been recently incorporated in the clinical management of Chagas disease, the rationale basis that supports this indication is poorly understood. Thus, we investigated the effect of an aerobic exercise on the parasitism, inflammation and oxidative tissue damage in a murine model of Trypanosoma cruzi-induced skeletal myositis. Wistar rats were randomized into four groups: trained not infected (TNI) and infected (TI), sedentary not infected (SNI) and infected (SI). A running training program was administered 5days/week for 9 weeks. Then, infected animals were inoculated with T. cruzi and followed up for another 9 weeks. Exercise training induced beneficial adaptations by increasing time to fatigue and lactate threshold in TNI and TI animals. SI animals presented higher parasitemia, skeletal muscle parasitism, cell necrosis, leukocyte infiltration, cytokines levels, reactive oxygen species and nitric oxide production, thiobarbituric acid reactive substances, carbonyl proteins, myosin heavy chain I depletion, and increased catalase (CAT) and superoxide dismutase (SOD) activities. Beyond attenuation in all these variables, TI animals showed reduced TNF-α, CCL-2/MCP-1 and CX3CL1, and increased IL-10 muscle levels. Furthermore, these animals presented higher CAT and SOD activities and reduced lipid and protein oxidation. Taken together, our findings indicated that exercise training induced a protective phenotype in T. cruzi-infected mice, enhancing host defenses against the parasite and attenuating the pathological remodeling associated with skeletal myositis, aspects potentially associated to an improved immunological and redox balance in infected animals.
Asunto(s)
Enfermedad de Chagas/inmunología , Enfermedad de Chagas/terapia , Terapia por Ejercicio/métodos , Trypanosoma cruzi , Animales , Citocinas/metabolismo , Inflamación/metabolismo , Interleucina-10/metabolismo , Masculino , Ratones , Músculo Esquelético/patología , Óxido Nítrico/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Carrera , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
AIMS: The rational basis that explains the benefits of exercise therapy on Chagas cardiomyopathy (ChC) is poorly understood. This study investigated the impact of an exercise program on exercise performance, heart parasitism, immunoinflammatory response, fibrogenesis, oxidative damage, and cardiomyocytes contractility in experimental ChC. MAIN METHODS: Wistar rats were subjected to a 9-week treadmill running training and challenged with Trypanosoma cruzi. Control animals remained sedentary. Physical and metabolic performance, cardiac morphology, cytokines, chemokines, nitric oxide, oxidative tissue damage, cardiomyocyte morphology and contractility were analyzed. KEY FINDINGS: Exercise training was efficient to improve physical performance and anaerobic threshold in trained animals. By increasing cardiac and serum levels of cytokines (TNF-α, IFN-γ, and IL-6), chemokines (MCP-1 and CX3CL1), the myocardial activity catalase and superoxide dismutase, and reducing lipid and protein oxidation in cardiac tissue, exercise training seem to be a beneficial strategy to mitigate the progression and severity of Chagas-associated cardiomyopathy. SIGNIFICANCE: The protective adaptations to the host triggered by exercise training contributed to reduce cardiac parasitism, inflammation, fibrosis and cardiomyocytes atrophy. Although exercise training does not affect nitric oxide levels in cardiac tissue from infected animals, this strategy enhanced the efficiency of endogenous antioxidant mechanisms, restricting oxidative tissue damage with positive repercussions to cardiomyocytes biomechanics in rats.
Asunto(s)
Antioxidantes/metabolismo , Cardiomiopatía Chagásica/metabolismo , Cardiomiopatía Chagásica/terapia , Terapia por Ejercicio/métodos , Inflamación/patología , Umbral Anaerobio , Animales , Cardiomiopatía Chagásica/patología , Quimiocinas/metabolismo , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Masculino , Miocardio/patología , Miocitos Cardíacos/patología , Parasitemia/sangre , Parasitemia/parasitología , Ratas , Ratas Wistar , Conducta Sedentaria , Trypanosoma cruzi , Remodelación VentricularRESUMEN
OBJECTIVES: This study investigated the combined effects of benznidazole (BZ) and ibuprofen (IB) on the oxidative and inflammatory status of the cardiac tissue in vivo. METHODS: Swiss mice were randomized in groups receiving BZ (100 mg/kg) and IB (400 mg/kg) alone or combined (BZ + IB 200 or 400 mg/kg). Control animals were concurrently treated with 1% carboxymethyl cellulose. All treatments were administered orally for 7 days. KEY FINDINGS: BZ treatment increased cardiac production of nitrogen/oxygen-reactive species, malondialdeyde, carbonyl proteins, prostaglandins as well as the activities of catalase, superoxide dismutase and glutathione peroxidase. These parameters were attenuated by IB, with the best results at higher dose. Individually, BZ and IB significantly reduced the tissue levels of chemokine ligand 2, tumour necrosis factor-α and IL-10, but no reduction was observed when the treatments were combined. CONCLUSIONS: BZ triggers an oxidative and nitrosative route, which is associated with increased prostaglandin synthesis and marked damages to the lipids and proteins of the cardiac tissue. IB treatment attenuated reactive stresses triggered by BZ, which was an independent effects of this drug on the endogenous antioxidant enzymes. Individually, but not together, BZ and IB reduced the cardiac inflammatory status, indicating a beneficial and complex drug interaction.
Asunto(s)
Ibuprofeno/farmacología , Inflamación/tratamiento farmacológico , Nitroimidazoles/farmacología , Estrés Oxidativo/efectos de los fármacos , Administración Oral , Animales , Antioxidantes/metabolismo , Catalasa/metabolismo , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/farmacología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Glutatión Peroxidasa/metabolismo , Ibuprofeno/administración & dosificación , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacología , Inflamación/patología , Masculino , Ratones , Nitroimidazoles/administración & dosificación , Distribución Aleatoria , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
BACKGROUND: The mechanisms responsible for the cardiac dysfunction associated with dietary protein restriction (PR) are poorly understood. Thus, this study was designed to evaluate the effects of PR on calcium kinetics, basal and ß-adrenergic contractility in murine ventricular cardiomyocytes. METHODS: After breastfeeding male Fisher rats were distributed into a control group (CG, n = 20) and a protein-restricted group (PRG, n = 20), receiving isocaloric diets for 35 days containing 15% and 6% protein, respectively. Biometric and hemodynamic variables were measured. After euthanasia left ventricles (LV) were collected for histopathological evaluation, SERCA2a expression, cardiomyocytes contractility and Ca(2+)sparks analysis. RESULTS: PRG animals showed reduced general growth, increased heart rate and arterial pressure. These animals presented extracellular matrix expansion and disorganization, cardiomyocytes hypotrophy, reduced amplitudes of shortening and maximum velocity of contraction and relaxation at baseline and after ß-adrenergic stimulation. Reduced SERCA2a expression as well as higher frequency and lower amplitude of Ca(2+)sparks were observed in PRG cardiomyocytes. CONCLUSION: The observations reveal that protein restriction induces marked myocardial morphofunctional damage. The pathological changes of cardiomyocyte mechanics suggest the potential involvement of the ß-adrenergic system, which is possibly associated with changes in SERCA2a expression and disturbances in Ca(2+) intracellular kinetics.
Asunto(s)
Calcio/metabolismo , Proteínas en la Dieta/administración & dosificación , Regulación hacia Abajo , Miocitos Cardíacos/fisiología , Receptores Adrenérgicos beta/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Animales , Masculino , Miocitos Cardíacos/metabolismo , Ratas , Ratas Endogámicas F344RESUMEN
Protein restriction (PR) is associated with cardiovascular diseases. The purpose of this study was to investigate the effects on single ventricular cardiomyocyte contractile function of a short-term PR after weaning. Male Fischer rats that were 28 days old were randomly divided into a control group (CG, n = 16) and a protein-restricted group (PRG, n = 16). After weaning, CG and PRG animals received isocaloric diets containing 15 and 6% protein, respectively, for 35 days. Biometric parameters were then measured, and the hearts were removed for the analysis of contractile function and calcium transient in isolated cardiomyocytes of the left ventricule (LV), and the quantification of calcium and collagen fibers in LV myocardium. PRG animals had lower body weight (BW) and LV weight (LVW), an increased LVW to BW ratio and a higher proportion of collagen fibers than CG animals. PRG animals exhibited reduced tissue levels of calcium, reduced the length, width and volume of cardiomyocytes and their sarcomere length compared to CG animals. Cardiomyocytes from PRG animals had a lower amplitude of shortening, a slower time to the peak of shortening and a longer time to half-relaxation than those from the CG. Cardiomyocytes from PRG animals also presented a lower peak of calcium transient and a longer calcium transient decay time than CG animals. Taken together, the results indicate that short-term PR after weaning induces a marked structural remodeling of the myocardium parenchyma and stroma that coexists with contractile dysfunctions in single LV cardiomyocytes of rats, which is probably associated with pathological changes of the intracellular calcium kinetics, rather than inadequate available amounts of this mineral in cardiac tissue.
Asunto(s)
Calcio/metabolismo , Enfermedades Cardiovasculares/etiología , Dieta con Restricción de Proteínas/efectos adversos , Contracción Miocárdica/fisiología , Miocitos Cardíacos/fisiología , Desnutrición Proteico-Calórica/etiología , Animales , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Modelos Animales de Enfermedad , Ventrículos Cardíacos/citología , Masculino , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Desnutrición Proteico-Calórica/metabolismo , Desnutrición Proteico-Calórica/fisiopatología , Distribución Aleatoria , Ratas , Ratas Endogámicas F344 , DesteteRESUMEN
BACKGROUND: This study investigates morphofunctional adaptations of the heart stroma and parenchyma in rats that are chronically infected with Trypanosoma cruzi. METHODS: Four-month-old male Wistar rats were randomized into control (n=14) and infected (n=14) groups. Infected animals were inoculated with T. cruzi Y strain. After 9 weeks, the animals were euthanized, and the right atrium (RA) and left ventricle (LV) were removed for biochemical, stereological, and cardiomyocyte mechanical analyses. RESULTS: Infected animals presented cardiomyocyte atrophy and myocardial fibrosis. For these animals, the total volume, length, surface area, and cross-sectional area of cardiomyocytes were significantly reduced, and the total interstitial and collagen volumes were significantly increased in the RA and LV compared to the controls. The total volume and length of blood vessels were significantly increased in the LV, and the total blood vessel surface area was significantly higher in the RA of infected animals. RA and LV cardiomyocytes from infected animals exhibited a significant reduction in cell shortening (43.02% and 24.98%, respectively), prolongation of the time to the peak of contraction (17.09%) and the time to half relaxation (23.68%) compared to non-infected animals. Lipid hydroperoxides, but not mineral concentrations, were significantly increased in the RA and LV from infected animals, showing an inverse correlation with cell shortening. CONCLUSIONS: T. cruzi infection induces global structural remodeling of the RA and LV in rats. This remodeling coexists with cardiomyocyte contractility dysfunction, which is possibly related to the abnormal organization of the myocardial stroma and increased cellular lipid peroxidation.
Asunto(s)
Forma de la Célula , Cardiomiopatía Chagásica/patología , Miocitos Cardíacos/patología , Células del Estroma/patología , Trypanosoma cruzi/patogenicidad , Remodelación Ventricular , Animales , Atrofia , Cardiomiopatía Chagásica/metabolismo , Cardiomiopatía Chagásica/fisiopatología , Cardiomiopatía Chagásica/virología , Vasos Coronarios/patología , Vasos Coronarios/virología , Modelos Animales de Enfermedad , Fibrosis , Atrios Cardíacos/patología , Atrios Cardíacos/virología , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/virología , Peroxidación de Lípido , Masculino , Contracción Miocárdica , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/virología , Ratas , Ratas Wistar , Células del Estroma/metabolismo , Células del Estroma/virología , Factores de Tiempo , VirulenciaRESUMEN
This study investigated the effects of Trypanosoma cruzi infection on pancreatic morphology and glucose metabolism at rest and during exercise. Wistar rats were randomized into control (CG=10) and infected (IG=10) groups. The IG animals were inoculated with T. cruzi Y strain (300,000 trypomastigotes/50 g). After 9 weeks, the animals were subjected to glucose (OGTT) and insulin (ITT) tolerance tests and a treadmill running protocol. Blood glucose, lactate and time to fatigue were determined. After euthanasia, the pancreases were removed for morphological and biochemical analyses. The IG presented abnormal glucose kinetics in OGTT and a similar glucose curve in ITT compared to the CG. During the exercise test, the IG showed anticipation of time to fatigue. At the point of fatigue, no difference was found in blood glucose and lactate between the groups. There was a significant correlation between lactate levels and the time to fatigue. The IG presented marked pancreatic inflammation, fibrosis and protein oxidation. The number of ß cells in the IG animals was not reduced. T. cruzi infection impaired pancreas morphology and glucose metabolism at rest and during exercise in rats, which could constitute an additional mechanism in the induction of exercise intolerance in Chagas' disease.
Asunto(s)
Glucemia/metabolismo , Enfermedad de Chagas/sangre , Islotes Pancreáticos/patología , Enfermedades Parasitarias en Animales/sangre , Condicionamiento Físico Animal/fisiología , Trypanosoma cruzi/fisiología , Animales , Enfermedad de Chagas/parasitología , Modelos Animales de Enfermedad , Prueba de Esfuerzo , Fibrosis/patología , Prueba de Tolerancia a la Glucosa , Islotes Pancreáticos/metabolismo , Masculino , Estrés Oxidativo , Enfermedades Parasitarias en Animales/parasitología , Carbonilación Proteica/fisiología , Ratas , Ratas Wistar , Descanso/fisiologíaRESUMEN
The aim of this study was to investigate the effects of Trypanosoma cruzi (T. cruzi) infection on myocardial morphology, single cardiomyocyte contractile function and exercise tolerance in rats. Adult Wistar rats were randomized into control (n = 14) and infected (n = 14) groups. Infected animals were inoculated with T. cruzi Y strain (300,000 trypomastigotes/50 g body weight). After 9 weeks, the animals were subjected to a treadmill running protocol. Then, the right atrium (RA) and left ventricle (LV) were removed for morphological and cell contractile evaluation. The infected animals exhibited a significant reduction in distance travelled, total time to fatigue and workload. In addition, these animals had hypertrophy, increased myocardial cellularity, and an increase in the proportion of collagen and blood vessels. RA and LV myocytes from infected animals showed marked contractile dysfunction under basal conditions and a reduced contractile response to ß-adrenergic stimulation. The workload of infected animals was correlated closely with the amplitude of cell shortening of RA and LV myocytes. T. cruzi infection influenced the myocardial morphology and the mechanical properties of RA and LV single myocytes negatively and reduced exercise tolerance. Single cardiomyocyte contractile dysfunction could constitute an additional mechanism of cardiac impairment and reduced exercise tolerance in this infection.