RESUMEN
ABSTRACT: Myocardial infarction (MI) and pulmonary arterial hypertension (PAH) are 2 prevalent cardiovascular diseases. In both conditions, oxidative stress is associated with a worse prognosis. Pterostilbene (PTE), an antioxidant compound, has been studied as a possible therapy for cardiovascular diseases. This study aims to evaluate the effect of PTE on oxidative stress in the hearts of animals with MI and in the lungs of animals with PAH. Male Wistar rats were used in both models. In the MI model, the experimental groups were sham, MI, and MI + PTE. In the PAH model, the experimental groups were control, PAH, and PAH + PTE. Animals were exposed to MI through surgical ligation of the left coronary artery, or to PAH, by the administration of monocrotaline (60 mg/kg). Seven days after undergoing cardiac injury, the MI + PTE animals were treated with PTE (100 mg/kg day) for 8 days. After this, the heart was collected for molecular analysis. The PAH + PTE animals were treated with PTE (100 mg/kg day) for 14 days, beginning 7 days after PAH induction. After this, the lungs were collected for biochemical evaluation. We found that PTE administration attenuated the decrease in ejection fraction and improved left ventricle end-systolic volume in infarcted animals. In the PAH model, PTE improved pulmonary artery flow and decreased reactive oxygen species levels in the lung. PTE administration promoted protective effects in terms of oxidative stress in 2 experimental models of cardiac diseases: MI and PAH. PTE also improved cardiac function in infarcted rats and pulmonary artery flow in animals with PAH.
Asunto(s)
Antioxidantes , Modelos Animales de Enfermedad , Pulmón , Infarto del Miocardio , Miocardio , Estrés Oxidativo , Hipertensión Arterial Pulmonar , Ratas Wistar , Estilbenos , Animales , Estrés Oxidativo/efectos de los fármacos , Masculino , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/fisiopatología , Estilbenos/farmacología , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/metabolismo , Antioxidantes/farmacología , Miocardio/metabolismo , Miocardio/patología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Arteria Pulmonar/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Presión Arterial/efectos de los fármacos , MonocrotalinaRESUMEN
This study explored the effect of pterostilbene (PTS) complexed with hydroxypropyl-ß-cyclodextrin (HPßCD) on right heart function, glutathione and glutaredoxin systems, and the expression of redox-sensitive proteins involved with regulation calcium levels in the experimental model of pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). After 7 days of PAH induction, rats received daily doses of the PTS:HPßCD complex (corresponding to 25, 50, or 100 mg·kg-1 of PTS) or vehicle (control group, CTR0) (an aqueous solution containing HPßCD; CTR0 and MCT0 (MCT group that did not receive PTS treatment)) via oral administration for 2 weeks. The results showed that the PTS:HPßCD complex increased the content of reduced glutathione and the activity of glutathione-S-transferase and glutaredoxin in the right ventricle (RV) of MCT-treated rats in a dose-dependent manner. Additionally, at higher doses, it also prevented the reduction of stroke volume and cardiac output, prevented myocardial performance index (MPI) increase, reduced lipoperoxidation, reduced total phospholamban, and increased the expression of sarcoplasmic reticulum calcium ATPase in the RV of MCT-treated rats. These results demonstrate that the PTS:HPßCD complex has a dose-dependent antioxidant mechanism that results in improved cardiac function in experimental right heart failure. Our results open a field of possibilities to PTS administration as new therapeutic approach to conventional therapy for right ventricular dysfunction. Novelty Pterostilbene complexed with hydroxypropyl-ß-cyclodextrin could be a new therapeutic approach. Pterostilbene complexed with hydroxypropyl-ß-cyclodextrin reestablishes redox homeostasis through glutathione metabolism modulation, leading to an improved MPI in pulmonary arterial hypertension-provoked right heart failure.
Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Estrés Oxidativo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Estilbenos/uso terapéutico , 2-Hidroxipropil-beta-Ciclodextrina/uso terapéutico , Animales , Antioxidantes/farmacología , Calcio/metabolismo , Ecocardiografía , Glutatión/metabolismo , Ventrículos Cardíacos/efectos de los fármacos , Hipertensión Pulmonar/inducido químicamente , Peroxidación de Lípido , Masculino , Monocrotalina , Ratas , Ratas Wistar , Volumen SistólicoRESUMEN
OBJECTIVES: Pulmonary arterial hypertension (PAH) is a condition characterized by an increased resistance of pulmonary vasculature, culminating in an increase in pulmonary pressure. This process involves disturbances in lung redox homeostasis, causing progressive right heart failure. In this context, the use of natural antioxidants, such as those found in blueberries, may represent a therapeutic approach. The aim of this study was to evaluate the effect of blueberry extract (BB) on functional parameters and oxidative stress levels in rat lungs with induced PAH. METHODS: Forty-eight male Wistar rats (weighing 200 ± 20 g) were randomized into five groups: control, monocrotaline, monocrotalineâ¯+â¯BB 50, monocrotalineâ¯+â¯BB 100, and monocrotalineâ¯+â¯BB 200. PAH was induced by the administration of monocrotaline (60 mg/kg, intraperitoneal). Rats were treated with BB at doses of 50, 100, and 200 mg/kg via gavage for 5 wk (2 wk before monocrotaline and 3 wk after monocrotaline injection). At day 35, rats were submitted to echocardiography and catheterization. They were then sacrificed and lungs were harvested for biochemical analyses. RESULTS: BB increased the E/A ratio of blood flow across the tricuspid valve and tricuspid annular phase systolic excursion, as wells as decreased the mean pulmonary artery pressure of animals compared with the PAH group. Moreover, BB decreased total reactive species concentration and lipid oxidation, reduced activity of nicotinamide adenine dinucleotide phosphate oxidase and expression of xanthine oxidase, increased the activity of superoxide dismutase and restored sulfhydryl content in the animal lungs compared with those in the PAH group. Additionally, BB restored expression of the antioxidant transcriptional factor Nrf2 in the lungs of the animal subjects. Finally, BB normalized the endothelin receptor (ETA/ETB) expression ratio in the animal lungs, which were increased in the PAH group. CONCLUSION: Intervention with BB mitigated functional PAH outcomes through improvement of the pulmonary redox state. Our results provide a basis for future research on natural antioxidant interventions as a novel treatment strategy in PAH.
Asunto(s)
Antioxidantes/farmacología , Presión Arterial/efectos de los fármacos , Arándanos Azules (Planta)/química , Extractos Vegetales/farmacología , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Pulmón/irrigación sanguínea , Masculino , Monocrotalina/farmacología , Oxidación-Reducción/efectos de los fármacos , Hipertensión Arterial Pulmonar/fisiopatología , Arteria Pulmonar/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
After acute myocardial infarction (AMI), reactive oxygen species and oxidative stress have important roles in the progression to heart failure. As a therapeutic alternative, thyroid hormones (TH) revealed cardioprotective effects after AMI, including decreasing oxidative stress. Carvedilol beta-blocker, already used in the clinical treatment of AMI, also mitigate cardiac pathological remodelling. This study assessed the effects of post-AMI carvedilol and TH co-administration on oxidative stress and cardiac function as well as whether those effects were synergistic. Male Wistar rats were divided into five groups: sham-operated (SHAM), infarcted (MI), infarcted + TH (MI + TH), infarcted + carvedilol (MI + C) and infarcted + C + TH (MI + C + TH). Two days post-surgery, the SHAM and MI groups received saline, and treated groups received their respective treatments by gavage for 12 days. The animals were submitted to echocardiographic evaluation, ventricular catheterization and euthanized for heart collection to perform oxidative stress analysis. Treated groups improved for ejection fraction compared to the MI group. Carvedilol decreased the positive chronotropic TH effects in the MI + C + TH group. The MI and MI + C groups had increased reactive oxygen species and reduced sulfhydryl levels. Carvedilol and TH co-administration showed synergic effects in the MI + C + TH group, reducing reactive oxygen species levels and improving GSH/GSSG ratio. Moreover, co-treatment attenuated NADPH oxidase activity in the MI group. Therefore, this study showed for the first time that carvedilol and TH co-administration may improve redox balance and cardiac function after AMI. Such co-administration could represent a therapeutic strategy capable of preventing cardiac dysfunction and redox unbalance after AMI.
Asunto(s)
Carvedilol/farmacología , Corazón/efectos de los fármacos , Corazón/fisiopatología , Infarto del Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Hormonas Tiroideas/farmacología , Animales , Antioxidantes/metabolismo , Sinergismo Farmacológico , Electrocardiografía/efectos de los fármacos , Disulfuro de Glutatión/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Infarto del Miocardio/sangre , Infarto del Miocardio/fisiopatología , NADPH Oxidasas/metabolismo , Oxidación-Reducción , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Compuestos de Sulfhidrilo/metabolismo , Tirotropina/sangreRESUMEN
There is an increase in oxidative stress and apoptosis signaling during the transition from hypertrophy to right ventricular (RV) failure caused by pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). In this study, it was evaluated the action of copaiba oil on the modulation of proteins involved in RV apoptosis signaling in rats with PAH. Male Wistar rats (±170 g, n = 7/group) were divided into 4 groups: control, MCT, copaiba oil, and MCT + copaiba oil. PAH was induced by MCT (60 mg/kg intraperitoneally) and, 7 days later, treatment with copaiba oil (400 mg/kg by gavage) was given for 14 days. Echocardiographic and hemodynamic measurements were performed, and the RV was collected for morphometric evaluations, oxidative stress, apoptosis, and cell survival signaling, and eNOS protein expression. Copaiba oil reduced RV hypertrophy (24%), improved RV systolic function, and reduced RV end-diastolic pressure, increased total sulfhydryl levels and eNOS protein expression, reduced lipid and protein oxidation, and the expression of proteins involved in apoptosis signaling in the RV of MCT + copaiba oil as compared to MCT group. In conclusion, copaiba oil reduced oxidative stress, and apoptosis signaling in RV of rats with PAH, which may be associated with an improvement in cardiac function caused by this compound.
Asunto(s)
Apoptosis/efectos de los fármacos , Fármacos Cardiovasculares/farmacología , Fabaceae , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/prevención & control , Monocrotalina , Miocardio , Aceites de Plantas/farmacología , Disfunción Ventricular Derecha/prevención & control , Función Ventricular Derecha/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Fármacos Cardiovasculares/aislamiento & purificación , Modelos Animales de Enfermedad , Fabaceae/química , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Miocardio/metabolismo , Miocardio/patología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Aceites de Plantas/aislamiento & purificación , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/patología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
The aim of this study was to analyse the effect of sulforaphane (SFN) in cultures of adult cardiomyocytes, evaluating oxidative stress at different times. Cells were isolated, cultured, and divided into 4 groups: Control, SFN (5µM), H2O2 (5µM), and SFN+H2O2 (5µM both), and subdivided into groups undergoing 1 or 24â¯h of SFN incubation. After 1â¯h of incubation, reactive oxygen species production was 40% lower in the SFN group than the Control, and lipid peroxidation was 63% higher in the H2O2 group than the Control, and it was reduced in both of the SFN groups. The SOD activity was 59% higher in groups incubated for 24â¯h than in those incubated for 1â¯h. Protein expression of SOD-1 and SOD-2 was higher in the 24-h groups compared to the 1-h groups (55% and 24%, respectively). The Nrf2 protein expression in the 1-h groups was 17% higher than in the 24-h groups, and the SFN + H2O2 group had 40% more Nrf2 than the Control in the 1-h groups. Unlike Nrf2, the PGC-1α expression was 69% higher in the 24-h groups in relation to the 1-h groups. Regarding the 24-h groups, the SFN and SFN+H2O2 groups were higher than the Control (32% and 33%, respectively), and the SFN+H2O2 group was increased (21%) compared to H2O2. SFN had a protective action against oxidative damage, but had no effect on the antioxidant enzymes analyzed. The different responses in the expression of Nrf2 and PGC-1α in relation to the incubation times, draws attention to the importance of establishing a timeline of the action of SFN, since there appears to be a temporal difference in its mechanism in adult cardiomyocytes.