RESUMO
ABSTRACT: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance (PVR), imposing overload on the right ventricle (RV) and imbalance of the redox state. Our study investigated the influence of treatment with sulforaphane (SFN), found in cruciferous vegetables, on RV remodeling and redox homeostasis in monocrotaline (MCT)-induced PAH. Male Wistar rats were separated into 4 groups: control (CTR); CTR + SFN; MCT; and MCT + SFN. PAH induction was implemented by a single dose of MCT (60 mg/kg intraperitoneally). Treatment with SFN (2.5 mg/kg/day intraperitoneally) started on the seventh day after the MCT injection and persisted for 2 weeks. After 21 days of PAH induction, echocardiographic, hemodynamic, and oxidative stress evaluation was performed. The MCT group showed an increase in RV hypertrophy, RV systolic area, RV systolic, mean pulmonary artery pressure, and PVR and exhibited a decrease in the RV outflow tract acceleration time/ejection time ratio, RV fractional shortening, and tricuspid annular plane systolic excursion compared to CTR ( P < 0.05). SFN-treated PAH attenuated detrimental changes in tricuspid annular plane systolic excursion, mean pulmonary artery pressure, and PVR parameters. Catalase levels and the glutathione/Glutathione disulfide (GSSG) ratio were diminished in the MCT group compared to CTR ( P < 0.05). SFN increased catalase levels and normalized the glutathione/GSSG ratio to control levels ( P < 0.05). Data express the benefit of SFN treatment on the cardiac function of rats with PAH associated with the cellular redox state.
Assuntos
Modelos Animais de Doenças , Isotiocianatos , Monocrotalina , Oxirredução , Estresse Oxidativo , Ratos Wistar , Sulfóxidos , Função Ventricular Direita , Animais , Sulfóxidos/farmacologia , Isotiocianatos/farmacologia , Masculino , Função Ventricular Direita/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/farmacologia , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/tratamento farmacológico , Homeostase/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/induzido quimicamente , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/metabolismo , Ratos , Pressão Arterial/efeitos dos fármacos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/metabolismo , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/tratamento farmacológico , Disfunção Ventricular Direita/metabolismoRESUMO
ABSTRACT: Pulmonary artery hypertension (PAH) imposes right heart and lung detrimental remodeling which impairs cardiac contractility, physical effort tolerance, and survival. The effects of an early moderate-intensity continuous aerobic exercise training on the right ventricle and lung structure, and on contractility and the calcium (Ca2+) transient in isolated myocytes from rats with severe PAH induced by monocrotaline were analyzed. Rats were divided into control sedentary (CS), control exercise (CE), monocrotaline sedentary (MS), and monocrotaline exercise (ME) groups. Animals from control exercise and ME groups underwent a moderate-intensity aerobic exercise on a treadmill (60 min/d; 60% intensity) for 32 days, after a monocrotaline (60 mg/kg body weight i.p.) or saline injection. The pulmonary artery resistance was higher in MS than in control sedentary (1.36-fold) and was reduced by 39.39% in ME compared with MS. Compared with MS, the ME group presented reduced alveolus (17%) and blood vessel (46%) wall, fibrosis (25.37%) and type I collagen content (55.78%), and increased alveolus (52.96%) and blood vessel (146.97%) lumen. In the right ventricle, the ME group exhibited diminished hypertrophy index (25.53%) and type I collagen content (40.42%) and improved myocyte contraction [ie, reduced times to peak (29.27%) and to 50% relax (13.79%)] and intracellular Ca2+ transient [ie, decreased times to peak (16.06%) and to 50% decay (7.41%)] compared with MS. Thus, early moderate-intensity continuous aerobic exercise prevents detrimental remodeling in the right heart and lung increases in the pulmonary artery resistance and dysfunction in single myocyte contraction and Ca2+ cycling in this model.
Assuntos
Sinalização do Cálcio , Terapia por Exercício , Hipertrofia Ventricular Direita/prevenção & controle , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Hipertensão Arterial Pulmonar/terapia , Disfunção Ventricular Direita/prevenção & controle , Função Ventricular Direita , Remodelação Ventricular , Remodelação das Vias Aéreas , Animais , Pressão Arterial , Modelos Animais de Doenças , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Masculino , Miócitos Cardíacos/patologia , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/patologia , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Ratos Wistar , Resistência Vascular , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/patologia , Disfunção Ventricular Direita/fisiopatologiaRESUMO
BACKGROUND: The failing right ventricle (RV) does not respond like the left ventricle (LV) to guideline-directed medical therapy of heart failure, perhaps due to interventricular differences in their molecular pathophysiology. METHODS: Using the canine tachypacing-induced biventricular heart failure (HF) model, we tested the hypothesis that interventricular differences in microRNAs (miRs) expression distinguish failing RV from failing LV. RESULTS: Severe RV dysfunction was indicated by elevated end-diastolic pressure (11.3±2.5 versus 5.7±2.0 mm Hg; P<0.0001) and diminished fractional area change (24.9±7.1 versus 48.0±3.6%; P<0.0001) relative to prepacing baselines. Microarray analysis of ventricular tissue revealed that miR-21 and miR-221, 2 activators of profibrotic and proliferative processes, increased the most, at 4- and 2-fold, respectively, in RV-HF versus RV-Control. Neither miR-21 or miR-221 was statistically significantly different in LV-HF versus LV-Control. These changes were accompanied by more extensive fibrosis in RV-HF than LV-HF. To test whether miR-21 and miR-221 upregulation is specific to RV cellular response to mechanical and hormonal stimuli associated with HF, we subjected fibroblasts and cardiomyocytes isolated from normal canine RV and LV to cyclic overstretch and aldosterone. These 2 stressors markedly upregulated miR-21 and miR-221 in RV fibroblasts but not in LV fibroblasts nor cardiomyocytes of either ventricle. Furthermore, miR-21/221 knockdown significantly attenuated RV but not LV fibroblast proliferation. CONCLUSIONS: We identified a novel, biological difference between RV and LV fibroblasts that might underlie distinctions in pathological remodeling of the RV in biventricular HF.
Assuntos
Fibroblastos/metabolismo , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/metabolismo , MicroRNAs/metabolismo , Disfunção Ventricular Direita/metabolismo , Animais , Cães , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Miócitos Cardíacos/metabolismo , Regulação para Cima , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Esquerda/fisiologiaRESUMO
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.
Assuntos
Apoptose/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Fabaceae , Hipertensão Pulmonar/tratamento farmacológico , Hipertrofia Ventricular Direita/prevenção & controle , Monocrotalina , Miocárdio , Óleos de Plantas/farmacologia , Disfunção Ventricular Direita/prevenção & controle , Função Ventricular Direita/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Fármacos Cardiovasculares/isolamento & purificação , Modelos Animais de Doenças , Fabaceae/química , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertrofia Ventricular Direita/induzido quimicamente , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Óleos de Plantas/isolamento & purificação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Disfunção Ventricular Direita/induzido quimicamente , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/patologia , Proteína X Associada a bcl-2/metabolismoRESUMO
Although iron excess is toxic to the vasculature and even that pulmonary hypertension has been reported in this scenario, the role of iron overload per se remains to be clarified. This study aimed to test the effects of chronic iron-overload in rats on the morphophysiology of resistance pulmonary arteries (RPA) and right ventricle (RV) remodeling. Rats were injected with saline or iron-dextran (10, 100 and 200â¯mg/kg/day i.p.) for 28 days. Our results indicated increased circulating iron with significant lung deposits. Moreover, rats treated with the highest dose exhibited RV dysfunction and hypertrophy; inward remodeling and increased vasoconstriction of the RPA. Vascular hyperreactivity was accompanied by reduced nitric oxide (NO), and was reversed by incubation with Dimethylsulfoxide, Catalase and Tempol. The NADPH oxidase subunit gp91phox was increased due to iron-overload, and incubation with angiotensin II type-1 receptor (AT1) antagonist losartan not only reduced oxidative stress but also restored vascular function. Thus, we concluded that AT1 pathway plays a role in pulmonary vascular dysfunction by increasing oxidative stress and reducing NO bioavailability, thereby contributing to vascular remodeling and pulmonary hypertension of iron-overload. This finding should instigate future studies on the beneficial impacts of in vivo blockade of AT1 receptor under iron overload.