RESUMEN
The objective of this study was to explore the influence of the renin-angiotensin system on cardiac prooxidants and antioxidants levels and its association to autonomic imbalance induced by hyperthyroidism. Male Wistar rats were divided into four groups: control, losartan (10mg/kg/day by gavage, 28 day), thyroxine (T4) (12 mg/L in drinking water for 28 days), and T4+losartan. Spectral analysis (autonomic balance), angiotensin II receptor (AT1R), NADPH oxidase, Nrf2 and heme-oxygenase-1 (HO-1) myocardial protein expression, and hydrogen peroxide (H2O2) concentration were quantified. Autonomic imbalance induced by hyperthyroidism (~770%) was attenuated in the T4+losartan group (~32%) (P<0.05). AT1R, NADPH oxidase, H2O2, as well as concentration, Nrf2 and HO-1 protein expression were elevated (~172%, 43%, 40%, 133%, and 154%, respectively) in T4 group (P<0.05). H2O2 and HO-1 levels were returned to control values in the T4+losartan group (P<0.05). The overall results demonstrate a positive impact of RAS blockade in the autonomic control of heart rate, which was associated with an attenuation of H2O2 levels, as well as with a reduced counter-regulatory response of HO-1 in experimental hyperthyroidism.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Hipertiroidismo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptor de Angiotensina Tipo 1/fisiología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Animales , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Hipertiroidismo/tratamiento farmacológico , Masculino , Ratas , Ratas WistarRESUMEN
This study was conducted to analyse the redox status and redox-sensitive proteins that may contribute to a non-genomic mechanism of cardiac hypertrophy induction by hyperthyroidism. Wistar rats, treated with L-thyroxine (T4) during 2 weeks (12 mg·l(-1) in drinking water), presented cardiac hypertrophy (68% higher than control), without signals of liver or lung congestion. Myocardial reduction of the reduced glutathione: oxidized glutathione (GSSG) ratio (45%) (redox status) and elevation in hydrogen peroxide concentration (H(2) O(2) ) (28%) were observed in hyperthyroid as compared with the control. No significant difference was found in thioredoxin (Trx), Trx reductase activity and Nrf2 (a transcriptional factor) protein expression between groups. Redox-sensitive proteins, quantified using Western blot, presented the following results: increased p-ERK: total extracellular-regulated kinase (ERK) (200%) and Bax:Bcl-2 (62%) ratios and reduced total-Akt (63%) and p-Akt (53%) expressions in the hyperthyroid rats as compared with the control. The redox imbalance, associated with increased immunocontent of a protein related to maladaptative growth (ERK) and reduced immunocontent of protein related to cytoprotection/survival (Akt), may suggest that the molecular scenario could favour the decompensation process of cardiac hypertrophy induced by experimental hyperthyroidism.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Cardiomegalia/inducido químicamente , Hipertiroidismo/inducido químicamente , Tiroxina/efectos adversos , Animales , Western Blotting , Cardiomegalia/patología , Muerte Celular , Agua Potable/administración & dosificación , Glutatión/metabolismo , Disulfuro de Glutatión/metabolismo , Peróxido de Hidrógeno/metabolismo , Hipertiroidismo/patología , Sistema de Señalización de MAP Quinasas , Masculino , Modelos Animales , Oxidación-Reducción , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Tiorredoxinas/metabolismo , Tiroxina/administración & dosificación , Tiroxina/farmacología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
This study was conducted to test whether oxidative stress activates the intracellular protein kinase B (AKT1) signaling pathway, which culminates with cardiac hypertrophy in experimental hyperthyroidism. Male Wistar rats were divided into four groups: control, vitamin E, thyroxine (T(4)), and T(4)+vitamin E. Hyperthyroidism was induced by T(4) administration (12 mg/l in drinking water for 28 days). Vitamin E treatment was given during the same period via s.c. injections (20 mg/kg per day). Morphometric and hemodynamic parameters were evaluated at the end of the 4-week treatment period. Protein oxidation, redox state (reduced glutathione, GSH/glutathione dissulfide, GSSG), vitamin C, total radical-trapping antioxidant potential (TRAP), hydrogen peroxide (H2O2), and nitric oxide metabolites (NO(X)) were measured in heart homogenates. The p-AKT1/AKT1 ratio, p-glycogen-synthase kinase (GSK)3B/GSK3B ratio, FOS, and JUN myocardial protein expression were also quantified by western blot after 4 weeks. Increases in biochemical parameters, such as protein oxidation (41%), H2O2 (62%), and NO(X) (218%), and increase in the left ventricular end-diastolic pressure were observed in the T(4) group. T(4) treatment also caused a decrease in GSH/GSSG ratio (83%), vitamin C (34%), and TRAP (55%). These alterations were attenuated by vitamin E administration to the hyperthyroid rats. Expression of p-AKT1/AKT1, p-GSK3B/GSK3B, FOS, and JUN were elevated in the T(4) group (by 69, 37, 130, and 33% respectively), whereas vitamin E administration promoted a significant reduction in their expression. These results indicate that oxidative stress plays an important role in cardiac hypertrophy, and suggest redox activation of AKT1 and JUN/FOS signaling pathways with H2O2 acting as a possible intracellular mediator in this adaptive response to experimental hyperthyroidism.
Asunto(s)
Cardiomegalia/etiología , Modelos Animales de Enfermedad , Hipertiroidismo/complicaciones , Transducción de Señal , Animales , Ácido Ascórbico/metabolismo , Western Blotting , Cardiomegalia/metabolismo , Glutatión/metabolismo , Peróxido de Hidrógeno/metabolismo , Masculino , Oxidación-Reducción , Ratas , Ratas Wistar , Tiroxina/sangreRESUMEN
Thyroxine can cause cardiac hypertrophy by activating growth factors, such as IGF-I (insulin-like growth factor-I). Since oxidative stress is enhanced in the hyperthyroidism, it would control protein expression involved in this hypertrophy. Male Wistar rats were divided into four groups: (I) control, (II) vitamin E-supplemented (20 mg/kg/day subcutaneous), (III) hyperthyroid (thyroxine 12 mg/l, in drinking water), and (IV) hyperthyroid + vitamin E. After 4 weeks, the contractility and relaxation indexes of left ventricle (LV), and cardiac mass were increased by 54%, 60%, and 60%, respectively, in hyperthyroid group. An increase in lipid peroxidation (around 40%), and a decrease in total glutathione (by 20%) was induced by thyroxine and avoided by vitamin E administration. Superoxide dismutase (SOD) and glutathione-S-transferase (GST) activities were increased (by 83% and 54%, respectively) in hyperthyroid, and vitamin E avoided changes in SOD. Protein expression of SOD, GST, and IGF-I receptor (IGF-IR) were increased (by 87%, 84%, and 60%, respectively) by thyroxine, and vitamin E promoted a significant reduction in SOD and IGF-IR expression (by 36% and 17%, respectively). These results indicate that oxidative stress is involved in cardiac hypertrophy, and suggest a role for IGF-IR as a mediator of this adaptive response in experimental hyperthyroidism.
Asunto(s)
Cardiomegalia/patología , Peroxidación de Lípido/efectos de los fármacos , Estrés Oxidativo , Receptor IGF Tipo 1/metabolismo , Tiroxina/farmacología , Animales , Antioxidantes/farmacología , Peso Corporal , Cardiomegalia/inducido químicamente , Cardiomegalia/metabolismo , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Transferasa/metabolismo , Masculino , Oxidación-Reducción , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo , Tiroxina/sangre , Vitamina E/farmacologíaRESUMEN
Hyperthyroidism was induced in rats by l-thyroxine administration (12 mg/L in drinking water, 4 weeks). Animals were assessed hemodynamically, and heart, lung, and liver morphometry were performed. Lipid peroxidation (LPO) and protein oxidation (carbonyls) were measured in heart homogenates. It was quantified glutathione (GSH) metabolism, and antioxidant enzyme activities its and protein expression (by Western blot). At the end of treatment, it was observed cardiac hypertrophy, elevation of left ventricular systolic and end diastolic pressures, lung and liver congestion. LPO and carbonyls were increased in the hyperthyroid group, and GSH was decreased by 46% in the fourth week. Myocardial oxidative stress time course analysis revealed that it was increased in the second week of treatment. Antioxidant enzyme activities elevation was accompanied by protein expression induction in the hyperthyroid group in the fourth week. These results imply that hyperthyroidism generates myocardial dysfunction associated with oxidative stress inducing antioxidant enzyme activities and protein expression.
Asunto(s)
Antioxidantes/metabolismo , Glutatión/metabolismo , Hipertiroidismo/metabolismo , Miocardio/enzimología , Animales , Catalasa/metabolismo , Glutatión Transferasa/metabolismo , Cardiopatías/complicaciones , Hipertiroidismo/inducido químicamente , Hipertiroidismo/complicaciones , Peroxidación de Lípido , Miocardio/metabolismo , Oxidación-Reducción , Ratas , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , TiroxinaRESUMEN
The present study examines which egocentric coordinate system determines the border between the disturbed 'contralateral' and the normal 'ipsilateral' side in patients with hemineglect. Based on the observation of significantly longer reaction times for saccades towards stimuli presented in the left visual field (LVF) in right brain-damaged patients with hemineglect, stimuli were presented randomly to the LVF or RVF and the corresponding saccadic reaction times (SRTs) were compared. Beginning with the standard body position generally used for the investigation of neglect patients, where the midlines of head, trunk and visual field are parallel and oriented straight towards the middle of the projection screen, the spatial relation between orientation of head and trunk midlines and location of the target stimuli was systematically varied while holding the retinal projection of the stimuli constant. The deficit in SRTs towards the LVF in 4 right brain-damaged patients with left-sided hemineglect could be compensated for by turning the patients' trunk to the left, such that both LVF and RVF-stimuli were projected to the right, ipsilateral side of trunk space. The results suggest that the spatial orientation of the trunk midline divides our normal perception of space into an egocentric 'left' and an egocentric 'right' sector and seems to be the decisive factor for determining the neglected 'contralateral' part of space in patients with brain-damage. They indicate that the trunk midline constitutes the physical anchor for calculation of the internal egocentric coordinate frame for representing body position with respect to external objects. The hypothesis of Ventre et al. (1984) that deficient reactions to contralaterally located stimuli in neglect patients could be the result of a displacement of these egocentric coordinates towards the non-neglected, ipsilateral side is discussed.