RESUMO
Inflammatory pathways of Toll-like receptor 4 (TLR4) and NLRP3 inflammasome contribute to acute myocardial infarction (AMI) pathophysiology. The hypoxia-inducible factor 1α (HIF-1α), however, is a key transcription factor related to cardioprotection. This study aimed to compare the influence of carvedilol and thyroid hormones (TH) on inflammatory and HIF-1α proteins and on cardiac haemodynamics in the infarcted heart. Male Wistar rats were allocated into five groups: sham-operated group (SHAM), infarcted group (MI), infarcted treated with the carvedilol group (MI + C), infarcted treated with the TH group (MI + TH), and infarcted co-treated with the carvedilol and TH group (MI + C + TH). Haemodynamic analysis was assessed 15 days post-AMI. The left ventricle (LV) was collected for morphometric and Western blot analysis. The MI group presented LV systolic pressure reduction, LV end-diastolic pressure elevation, and contractility index decrease compared to the SHAM group. The MI + C, MI + TH, and MI + C + TH groups did not reveal such alterations compared to the SHAM group. The MI + TH and MI + C + TH groups presented reduced MyD88 and NLRP3 and increased HIF-1α levels. In conclusion, all treatments preserve the cardiac haemodynamic, and only TH, as isolated treatment or in co-treatment with carvedilol, was able to reduce MyD88 and NLRP3 and increase HIF-1α in the infarcted heart.
Assuntos
Fator 88 de Diferenciação Mieloide , Infarto do Miocárdio , Animais , Masculino , Ratos , Carvedilol/farmacologia , Carvedilol/uso terapêutico , Fator 88 de Diferenciação Mieloide/metabolismo , Infarto do Miocárdio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos Wistar , Hormônios TireóideosRESUMO
Pulmonary arterial hypertension (PAH) is characterized by increased resistance of the pulmonary vasculature and afterload imposed on the right ventricle (RV). Two major contributors to the worsening of this disease are oxidative stress and mitochondrial impairment. This study aimed to explore the effects of monocrotaline (MCT)-induced PAH on redox and mitochondrial homeostasis in the RV and brain and how circulating extracellular vesicle (EV) signaling is related to these phenomena. Wistar rats were divided into control and MCT groups (60 mg/kg, intraperitoneal), and EVs were isolated from blood on the day of euthanasia (21 days after MCT injections). There was an oxidative imbalance in the RV, brain, and EVs of MCT rats. PAH impaired mitochondrial function in the RV, as seen by a decrease in the activities of mitochondrial complex II and citrate synthase and manganese superoxide dismutase (MnSOD) protein expression, but this function was preserved in the brain. The key regulators of mitochondrial biogenesis, namely, proliferator-activated receptor gamma coactivator 1-alpha and sirtuin 1, were poorly expressed in the EVs of MCT rats, and this result was positively correlated with MnSOD expression in the RV and negatively correlated with MnSOD expression in the brain. Based on these findings, we can conclude that the RV is severely impacted by the development of PAH, but this pathological injury may signal the release of circulating EVs that communicate with different organs, such as the brain, helping to prevent further damage through the upregulation of proteins involved in redox and mitochondrial function.
Assuntos
Vesículas Extracelulares , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Animais , Encéfalo , Modelos Animais de Doenças , Homeostase , Hipertensão Pulmonar/induzido quimicamente , Mitocôndrias , Monocrotalina/toxicidade , Oxirredução , Estresse Oxidativo , Ratos , Ratos WistarRESUMO
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
Our aim was to investigate transitory and delayed exercise effects on serum extracellular vesicles (EVs) in aging process. Male Wistar rats of 3-, 21-, and 26-month old were allocated into exercised and sedentary groups. The exercise protocol consisted in a daily moderate treadmill exercise (20 min daily during 2 weeks). Trunk blood was collected 1 and 18 h after the last exercise session, and circulating EVs were obtained. CD63 levels and acetylcholinesterase (AChE) activity were used as markers of exosome, a subtype of EVs. In addition, the quantification of amyloid-ß (Aß) levels and the oxidative status parameters, specifically reactive species content, superoxide dismutase (SOD) activity, and SOD1 content were evaluated. Aged rats showed reduced CD63 levels and increased AChE activity in circulating exosomes compared to young ones. Moreover, higher reactive species levels were found in circulating EVs of aged rats. Delayed exercise effects were observed on peripheral EVs, since CD63, reactive species content, and AChE activity were altered 18 h after the last exercise session. Our results suggest that the healthy aging process can modify circulating EVs profile, and exercise-induced beneficial effects may be related to its modulation on EVs.