Inhibition of IL-1 Ameliorates Cardiac Dysfunction and Arrhythmias in a Murine Model of Kawasaki Disease.

BACKGROUND: Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis often associated with cardiac sequelae, including arrhythmias. Abundant evidence indicates a central role for IL (interleukin)-1 and TNFα (tumor necrosis factor-alpha) signaling in the formation of arterial lesions in KD. We aimed to investigate the mechanisms underlying the development of electrophysiological abnormalities in a murine model of KD vasculitis. METHODS: Lactobacillus casei cell wall extract-induced KD vasculitis model was used to investigate the therapeutic efficacy of clinically relevant IL-1Ra (IL-1 receptor antagonist) and TNFα neutralization. Echocardiography, in vivo electrophysiology, whole-heart optical mapping, and imaging were performed. RESULTS: KD vasculitis was associated with impaired ejection fraction, increased ventricular tachycardia, prolonged repolarization, and slowed conduction velocity. Since our transcriptomic analysis of human patients showed elevated levels of both IL-1ß and TNFα, we asked whether either cytokine was linked to the development of myocardial dysfunction. Remarkably, only inhibition of IL-1 signaling by IL-1Ra but not TNFα neutralization was able to prevent changes in ejection fraction and arrhythmias, whereas both IL-1Ra and TNFα neutralization significantly improved vasculitis and heart vessel inflammation. The treatment of L casei cell wall extract-injected mice with IL-1Ra also restored conduction velocity and improved the organization of Cx43 (connexin 43) at the intercalated disk. In contrast, in mice with gain of function of the IL-1 signaling pathway, L casei cell wall extract induced spontaneous ventricular tachycardia and premature deaths. CONCLUSIONS: Our results characterize the electrophysiological abnormalities associated with L casei cell wall extract-induced KD and show that IL-1Ra is more effective in preventing KD-induced myocardial dysfunction and arrhythmias than anti-TNFα therapy. These findings support the advancement of clinical trials using IL-1Ra in patients with KD.

Effects of Intravenously Administered Plasma from Exercise-Trained Donors on Microglia and Cytokines in a Transgenic Rat Model of Alzheimer's Disease.

Background: Microglia and inflammation play a significant role in Alzheimer's disease (AD). Physical exercise and peripheral signals can influence microglial activity in the brain. Modulating the inflammatory response in the brain may provide therapeutic approaches for AD. Objective: To assess the effects of intravenously administered blood plasma from exercise-trained donor rats on cognitive function, microglia, and cytokine levels in an AD rat model at two different pathological stages; an early pre-plaque stage and a later stage closer to the emergence of extracellular plaques. Methods: Male transgenic McGill-R-Thy1-APP rats aged 2 and 5 months received 14 injections over 6 weeks: 1) plasma from exercise-trained rats (ExPlas), 2) plasma from sedentary rats (SedPlas), or 3) saline. Cognitive function was evaluated in a novel object recognition task. Microglia count and morphology were analyzed in cornu ammonis, dentate gyrus, entorhinal cortex, and subiculum. Amyloid plaque number and size were assessed in the rats with the later treatment start. A multiplex assay was used to measure 23 cytokines in cornu ammonis. Results: In rats treated from 2 months of age, ExPlas and SedPlas increased number and length of microglial branches in cornu ammonis and dentate gyrus compared to saline. Only ExPlas-treated rats exhibited similar changes in subiculum, while entorhinal cortex showed no differences across treatments. Microglia count remained unaffected. In rats treated from 5 months of age, there were no significant differences in microglia count or morphology or the number or size of amyloid plaques in any brain region. Compared to both other treatments in early pre-plaque stage rats, SedPlas increased TNF-α levels. ExPlas upregulated GM-CSF, IL-18, and VEGF, while SedPlas increased IL-10 compared to saline. In later-stage rats, ExPlas upregulated IL-17, and SedPlas upregulated TNF-α compared to saline. There were no effects of treatments on recognition memory. Conclusions: Intravenous injections of blood plasma from exercise-trained and sedentary donors differentially modulated microglial morphology and cytokine levels in the AD rat model at an early pre-plaque stage of pathology. Exercised plasma may reduce proinflammatory TNF-α signaling and promote microglial responses to early Aß accumulation but the lack of treatment effects in the later-stage rats emphasizes the potential importance of treatment timing.

Treino de Força Reduz Stress Oxidativo Cardíaco e Renal em Ratos com Hipertensão Renovascular / Strength Training Reduces Cardiac and Renal Oxidative Stress in Rats with Renovascular Hypertension

Resumo Fundamento O treino de força tem efeitos benéficos em doenças renais, além de ajudar a melhorar a defesa antioxidante em animais saudáveis. Objetivo Verificar se o treino de força reduz o dano oxidativo ao coração e rim contralateral para cirurgia de indução de hipertensão renovascular, bem como avaliar as alterações na atividade das enzimas antioxidantes endógenas superóxido dismutase (SOD), catalase (CAT) e glutationa peroxidase (GPx). Métodos Dezoito ratos machos foram divididos em três grupos (n=6/grupo): placebo, hipertenso e hipertenso treinado. Os animais foram induzidos a hipertensão renovascular através da ligação da artéria renal esquerda. O treino de força foi iniciado quatro semanas após a indução da hipertensão renovascular, teve 12 semanas de duração e foi realizada a 70% de 1RM. Depois do período de treino, os animais foram submetidos a eutanásia e o rim esquerdo e o coração foram retirados para realizar a quantificação de peróxidos de hidrogênio, malondialdeído e grupos sulfidrílicos, que são marcadores de danos oxidativos. Além disso, foram medidas as atividades das enzimas antioxidantes superóxido dismutase, catalase e glutationa peroxidase. O nível de significância adotado foi de 5% (p < 0,05). Resultados Depois do treino de força, houve redução de danos oxidativos a lipídios e proteínas, como pode-se observar pela redução de peróxidos de hidrogênio e níveis sulfidrílicos totais, respectivamente. Além disso, houve um aumento nas atividades das enzimas antioxidantes superóxido dismutase, catalase e glutationa peroxidase. Conclusão O treino de força tem o potencial de reduzir danos oxidativos, aumentando a atividades de enzimas antioxidantes. (Arq Bras Cardiol. 2021; 116(1):4-11)

Abstract Background Strength training has beneficial effects on kidney disease, in addition to helping improve antioxidant defenses in healthy animals. Objective To verify if strength training reduces oxidative damage to the heart and contralateral kidney caused by the renovascular hypertension induction surgery, as well as to evaluate alterations in the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) endogenous antioxidant enzymes. Methods Eighteen male rats were divided into three groups (n=6/group): sham, hypertensive, and trained hypertensive. The animals were induced to renovascular hypertension through left renal artery ligation. Strength training was initiated four weeks after the induction of renovascular hypertension, continued for a 12-weeks period, and was performed at 70% of 1RM. After the training period, the animals were euthanized and the right kidney and heart were removed for quantitation of hydroperoxides, malondialdehyde and sulfhydryl groups, which are markers of oxidative damage. In addition, the activity of SOD, CAT, and GPx antioxidant enzymes was also measured. The adopted significance level was 5% (p < 0.05). Results After strength training, a reduction in oxidative damage to lipids and proteins was observed, as could be seen by reducing hydroperoxides and total sulfhydryl levels, respectively. Furthermore, an increased activity of superoxide dismutase, catalase, and glutathione peroxidase antioxidant enzymes was observed. Conclusion Strength training is able to potentially reduce oxidative damage by increasing the activity of antioxidant enzymes. (Arq Bras Cardiol. 2021; 116(1):4-11)

Biomarker responses of cardiac oxidative stress to high intensity interval training in rats

Abstract Aim: The present study aimed to verify the cardiac oxidative stress biomarker responses to high-intensity interval training (HIIT) in rats. Methods: Sixteen male Wistar rats weighing 250 to 300 g were equally divided into two groups (8 animals/group): sedentary control (SC) and trained group (HIIT). The exercise protocol consisted of high-intensity swimming (14% of body weight, 20 s of activity with 10 s of pause performed 14 times) which was performed for 12 consecutive days. Results: The cardiac tissue concentrations of malondialdehyde and carbonylated proteins showed no significant changes; on the other hand, hydroperoxide levels were higher in the HIIT group than in the SC group. The activities of superoxide dismutase, catalase, and glutathione peroxidase enzymes and the levels of reduced glutathione and sulfhydryl remained unchanged. Conclusion: It is possible to conclude that short-term high-intensity interval training induces changes in the cardiac oxidative stress biomarker but with no effect on the antioxidant enzymes.

Short-term hiit does not promote oxidative stress or muscle damage / Hiit de corto plazo no promueve estrés oxidativo o daños musculares / Hiit de curto prazo não promove estresse oxidativo ou danos musculares

ABSTRACT Introduction: High intensity interval training (HIIT) is a method that is widely used today. Objective: The present study aimed to evaluate the effects of HIIT on markers of oxidative stress and muscle damage in rats. Methods: The sample consisted of 60-day-old Wistar rats, divided into two groups: a control group (n=8) and an HIIT group (n=8). The training consisted of fourteen 20-second swimming sessions (loaded with weights equivalent to 14% of their body weight) with 10-second intervals between each session, performed for 12 consecutive days. Results: HIIT induced a reduction (−17.75%) in thiobarbituric acid reactive substances (an oxidative stress marker) in hepatic tissue (p=0.0482). There was also a reduction (−31.80%) in the HIIT group in the level of superoxide dismutase enzyme activity in the liver (p=0.0375). However, there were no differences between the groups in catalase, glutathione peroxidase, glutathione reductase, the total content of SH sulfhydryls, hydroperoxides, or carbonylated proteins in the hepatic tissue. No significant differences were found in any of these markers in the gastrocnemius muscle. The muscle damage markers creatinine kinase and lactate dehydrogenase were also similar between the groups in the gastrocnemius. Conclusion: The conclusion was that that short-term HIIT does not cause oxidative stress or muscle damage. Level of evidence I; High-quality randomized clinical trial with or without statistically significant difference, but with narrow confidence intervals.

RESUMEN Introducción: El entrenamiento en intervalos de alta intensidad (HIIT) es un método muy utilizado actualmente. Objetivo: El presente estudio tuvo como objetivo evaluar los efectos del HIIT en corto plazo sobre marcadores de estrés oxidativo y daño muscular en ratones. Métodos: La muestra consistió en ratones Wistar con 60 días de edad, divididos en dos grupos: grupo control (n = 8) y grupo HIIT (n = 8). El entrenamiento consistió en catorce sesiones de natación de 20 segundos (con cargas equivalentes a 14% del peso corporal) con intervalos de 10 segundos entre cada sesión, realizadas durante 12 días consecutivos. Resultados: El HIIT indujo una reducción (-17,75%) de las sustancias reactivas al ácido tiobarbitúrico (un marcador de estrés oxidativo) en el tejido hepático (p = 0,0482). También hubo reducción (~31,80%) en el grupo HIIT en el nivel de enzima superóxido dismutasa en el hígado (p=0,0375). Sin embargo, no hubo diferencias entre los grupos con relación a catalasa, glutatión peroxidasa, glutatión reductasa, tenor total de sulfhidrilos SH, hidroperóxidos o proteínas carboniladas en el tejido hepático. No fue encontrada ninguna diferencia significativa en ninguno de esos marcadores en el músculo gastrocnemio. Los marcadores de lesión muscular, creatinina quinasa y lactato deshidrogenasa también fueron similares entre los grupos en el gastrocnemio. Conclusión: Fue posible concluir que el HIIT de corta duración no causa estrés oxidativo o daño muscular. Nivel de evidencia I; Estudio clínico aleatorizado de alta calidad con o sin diferencia estadísticamente significativa, pero con intervalos de información estrechos.

RESUMO Introdução: O treinamento intervalado de alta intensidade (HIIT) é um método muito utilizado atualmente. Objetivo: O presente estudo objetivou avaliar os efeitos do HIIT em curto prazo sobre marcadores de estresse oxidativo e dano muscular em ratos. Métodos: A amostra consistiu em ratos Wistar com 60 dias de idade, divididos em dois grupos: grupo controle (n = 8) e grupo HIIT (n = 8). O treinamento consistiu em quatorze sessões de natação de 20 segundos (com cargas equivalentes a 14% do peso corporal) com intervalos de 10 segundos entre cada sessão, realizadas por 12 dias consecutivos. Resultados: O HIIT induziu uma redução (-17,75%) das substâncias reativas ao ácido tiobarbitúrico (um marcador de estresse oxidativo) no tecido hepático (p = 0,0482). Houve também redução (-31,80%) no grupo HIIT no nível de enzima superóxido dismutase no fígado (p = 0,0375). No entanto, não houve diferenças entre os grupos com relação a catalase, glutationa peroxidase, glutationa redutase, teor total de sulfidrilas SH, hidroperóxidos ou proteínas carboniladas no tecido hepático. Nenhuma diferença significativa foi encontrada em qualquer um desses mascadores no músculo gastrocnêmio. Os marcadores de lesão muscular, creatinina quinase e lactato desidrogenase, também foram semelhantes entre os grupos no gastrocnêmio. Conclusão: Foi possível concluir que o HIIT de curta duração não causa estresse oxidativo ou dano muscular. Nível de evidência I; Estudo clínico randomizado de alta qualidade com ou sem diferença estatisticamente significante, mas com intervalos de informação estreitos.

Influence of antihypertensive pharmacological treatment on the acute cardiovascular responses to the resistance exercise in hypertensive middle-aged women

Abstract Aim: To investigate the hypothesis that the resistance exercise (RE) may be safer if the blood pressure (BP) is properly controlled through antihypertensive pharmacological treatment in hypertensive middle-aged women. Methods: The final sample was comprised of 19 hypertensive women, with an average age of 58±5 years and a body mass index of 29±5 Kg/m2. They were divided into three groups: controlled (n=6), uncompensated (n=8), and untreated (n=5). The subjects from all groups were submitted to a test of maximal strength on extensor chair and held a session of RE (knee extension, 3x12 to 60% 1RM) and the cardiovascular response (BP and heart rate) was monitored continuously by photoplethysmography during exercise and until five minutes after exercise (recovery). Results: Systolic BP (SBP) and diastolic BP (DBP) responses were lower in the controlled group compared to the other groups (p<0.05). The heart rate was not different between groups, while the double product was lower in the controlled group compared to the untreated group (p<0.05). The SBP and DBP peaks were lower in the controlled group compared to the other groups (p<0.05). Conclusion: The BP increases significantly during RE when the hypertension is not controlled. Pharmacological control was shown to be effective in preventing the increase of BP during the performance of the RE.