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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.

Sulforaphane (SFN) is a natural exogenous antioxidant from cruciferous vegetables already shown to improve cardiac function in cardiovascular diseases. The aim of this study was to analyze the effect of SFN treatment on the cardiac function in 2 experimental models of heart disease, ischemia/reperfusion (I/R) and myocardial infarction (MI), and whether an improvement of the cardiac function could be associated with a modulation of calcium-handling proteins. The study was divided into 2 main experiments: experiment 1, ex vivo with the I/R model and experiment 2, in vivo with the MI model. In the I/R model, rats were divided into control and SFN (0.5 mg/kg/d intraperitoneally for 3 days) groups, and the hearts were submitted to global ischemia (20 minutes) followed by reperfusion (20 minutes) in a Langendorff apparatus. SFN did not change left ventricle systolic and diastolic pressures but increased the contractility and relaxation indexes after 20 minutes of reperfusion. These functional changes were accompanied by a decreased protein expression of ryanodine receptor (RyR) and increased expression of p-phospholamban/phospholamban ratio, without alteration in the sarco/endoplasmic calcium ATPase expression. In the MI model, rats were randomly divided into Sham, MI (MI induced by left coronary artery ligation), Sham + SFN (5 mg/kg/d intraperitoneally for 25 days), and MI + SFN groups. Although SFN did not affect cardiac function, it led to a decreased RyR protein expression and reactive oxygen species levels in the left ventricular of the MI + SFN group. These data indicate that SFN modulates calcium-handling proteins and, thus, cardiac inotropism/lusitropism especially when administered previously to an ischemic event.

Enhanced sympathetic system activation mediated by norepinephrine (NE) contributes to adverse cardiac remodeling leading to oxidative stress and cell death, progressing to heart failure. Natural antioxidants may help maintain redox balance, attenuating NE-mediated cardiac cell damage. In the present study, we evaluated the effect of a blueberry extract (BBE) on H9c2 cardiac cells exposed to NE on cell death, oxidative stress status and its major signaling pathways. H9c2 cells were pre-incubated with 50 μg/ml of BBE for 4 h and maintained in the presence of 100 μM NE for 24 h. NE exposure resulted in increased caspase 3/7 activity. This was associated with reduced protein expression of antioxidants catalase, superoxide dismutase and glutathione peroxidase and increase in 4-hydroxynonenal adduct formation. NE led to increased activity of Protein kinase B (Akt), Forkhead box O3a and AMP-activated protein kinase alpha and decreased activity of Signal transducer and activator of transcription 3. BBE prevented caspases activation and abrogated NE-induced increase in oxidative stress, as well as attenuated the increase in Akt. Based on these findings, it is concluded that BBE promoted cardioprotection of H9c2 cells in an in vitro model of NE-induced oxidative damage, suggesting a cardioprotective role for BBE in response to NE exposure.

The main objective of this work was to evaluate whether Pleurotus albidus extract exerts influences on aorta artery tone by its antioxidant properties. The hearts and aortic arteries of male Wistar rats were removed for use in biochemical analysis and vascular reactivity. Both tissues were exposed to P. albidus extract at different concentrations for 30 min and were then exposed to a free radical generation system for 30 min. The extract reduced lipid peroxidation levels and increased catalase and glutathione peroxidase activity in cardiac tissue. In the aorta, P. albidus extract demonstrated a direct vasodilatory effect, which was associated with a reduction in nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity and an increase in sulfhydryl levels and nitric oxide synthase (NOS) activity. Our findings suggest that P. albidus extract has regulatory potential on aorta arteries, regulating the balance of NOX/NOS enzymes and then influencing vessel tone. Further studies are needed to determine the protective mechanisms of the extract.

Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary vascular resistance and right ventricle (RV) failure. In this context, oxidative stress is an essential element contributing to PAH’s pathophysiology. Thus, blueberry (BB), which has a high antioxidant capacity, emerges as a natural therapeutic approach in PAH. This work evaluated the effect of BB extract on redox balance in RV in a PAH’s animal model. Male Wistar rats (200 ± 20 g) (n = 72) were randomized into eight groups: control (CTR); monocrotaline (MCT); CTR and MCT treated at doses of 50, 100, and 200 mg/kg BB. PAH was induced by administration of MCT (60 mg/kg, intraperitoneal). Rats were treated with BB orally for 5 weeks (2 weeks before monocrotaline and 3 weeks after monocrotaline injection). On day 35, rats were submitted to echocardiography and catheterization, then euthanasia and RV harvesting for biochemical analyses. RV hypertrophy, observed in the MCT groups, was reduced with BB treatment. MCT elevated RV systolic pressure and pressure/time derivatives, while the intervention with BB decreased these parameters. PAH decreased RV output and pulmonary artery outflow acceleration/ejection time ratio, while increased RV diameters, parameters restored by BB treatment. Animals from the MCT group showed elevated lipid peroxidation and NADPH oxidase activity, outcomes attenuated in animals treated with BB, which also led to increased catalase activity. Treatment with BB partially mitigated PAH, which could be associated with improvement of RV redox state. Such findings constitute an advance in the investigation of the role of BB extract in chronic progressive cardiovascular diseases that involve the redox balance, such as PAH.

Cellular death and survival signaling plays a key role in the progress of adverse cardiac remodeling after acute myocardial infarction (AMI). Therapeutic strategies, such as co-treatment with beta-blocker carvedilol and thyroid hormones (THs), give rise to new approaches that can sustain the cellular homeostasis after AMI. Therefore, we sought to investigate the effects of carvedilol and TH co-administration on apoptosis and survival proteins and on cardiac remodeling after AMI. Male Wistar rats were distributed in 5 groups as follows: sham-operated group (SHAM), infarcted group (MI), infarcted plus carvedilol group (MI+C), infarcted plus TH group (MI+TH), and infarcted plus carvedilol and TH co-treatment group (MI+C+TH). Echocardiographic analysis was performed, and hearts were collected for western blot evaluation. The MI group presented systolic posterior wall thickness loss, an increase in the wall tension index, and an increase in atrial natriuretic peptide tissue levels than the SHAM group. However, in the MI+C+TH group, these parameters were equally to the SHAM group. Moreover, whereas the MI group showed Bax protein expression elevated in relation to the SHAM group, the MI+C+TH group presented Bax reduction and also Akt activation compared with the MI group. In addition, the MI+TH group revealed beta-1 adrenergic receptor (β1AR) upregulation compared with the MI and MI+C groups, whereas the MI+C+TH group presented lower levels of β1AR in relation to the SHAM and MI+TH groups. In conclusion, we suggest that carvedilol and TH co-administration may mediate its cardioprotective effects against adverse cardiac remodeling post-AMI through the Bax reduction, Akt activation, and β1AR decrease.

Sulforaphane is a natural compound that presents anti-inflammatory and antioxidant properties, including in the central nervous system (CNS). Astroglial cells are involved in several functions to maintain brain homeostasis, actively participating in the inflammatory response and antioxidant defense systems. We, herein, investigated the potential mechanisms involved in the glioprotective effects of sulforaphane in the C6 astrocyte cell line, when challenged with the inflammogen, lipopolysaccharide (LPS). Sulforaphane prevented the LPS-induced increase in the expression and/or release of pro-inflammatory mediators, possibly due to nuclear factor κB and hypoxia-inducible factor-1α activation. Sulforaphane also modulated the expressions of the Toll-like and adenosine receptors, which often mediate inflammatory processes induced by LPS. Additionally, sulforaphane increased the mRNA levels of nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO1), both of which mediate several cytoprotective responses. Sulforaphane also prevented the increase in NADPH oxidase activity and the elevations of superoxide and 3-nitrotyrosine that were stimulated by LPS. In addition, sulforaphane and LPS modulated superoxide dismutase activity and glutathione metabolism. Interestingly, the anti-inflammatory and antioxidant effects of sulforaphane were blocked by HO1 pharmacological inhibition, suggesting its dependence on HO1 activity. Finally, in support of a glioprotective role, sulforaphane prevented the LPS-induced decrease in glutamate uptake, glutamine synthetase activity, and glial-derived neurotrophic factor (GDNF) levels, as well as the augmentations in S100B release and Na+, K+ ATPase activity. To our knowledge, this is the first study that has comprehensively explored the glioprotective effects of sulforaphane on astroglial cells, reinforcing the beneficial effects of sulforaphane on astroglial functionality.

Vitamin C (Vit C) is an ideal antioxidant as it is easily available, water soluble, very potent, least toxic, regenerates other antioxidants particularly Vit E, and acts as a cofactor for different enzymes. It has received much attention due to its ability in limiting reactive oxygen species, oxidative stress, and nitrosative stress, as well as it helps to maintain some of the normal metabolic functions of the cell. However, over 140 clinical trials using Vit C in different pathological conditions such as myocardial infarction, gastritis, diabetes, hypertension, stroke, and cancer have yielded inconsistent results. Such a divergence calls for new strategies to establish practical significance of Vit C in heart failure or even in its prevention. For a better understanding of Vit C functioning, it is important to revisit its transport across the cell membrane and subcellular interactions. In this review, we have highlighted some historical details of Vit C and its transporters in the heart with a particular focus on heart failure in cancer chemotherapy.

Introdução: O estresse oxidativo está relacionado ao aparecimento de doenças cardiovasculares. Sedentarismo e obesidade predispõem ao aumento da formação de espécies reativas ao oxigênio e a atividade física vem sendo considerada como um fator de redução deste fator. Objetivo: Avaliar se uma sessão de exercício físico de baixa a moderada intensidade altera o stress oxidativo após 12 horas em mulheres com aumento do peso corporal. Método: Incluídas 30 mulheres sedentárias com excesso de peso corporal (IMC de 29±4,4kg/m2) divididas aleatoriamente em dois grupos. Após um jejum de 12 horas, as voluntárias fizeram uma primeira coleta de sangue. O grupo experimento foi submetido a uma sessão de exercício físico 12 horas após a primeira coleta de sangue. As voluntárias do grupo controle e experimento fizeram uma segunda coleta de sangue 24 horas após a primeira. Foram dosados Triglicerídeos, colesterol total, TBARS, carbonilas e sulfidrilas. Foram utilizados teste t para amostras independentes e dependentes e adotando como nível de significância 5%. Resultados: O exercício físico modificou a resposta de peroxidação lipídica na análise intergrupo (controle = Δ 0,49 (-0,18 - 0,81) vs experimento = Δ-0,09 (-0,58 - 0,21)) (p = 0,02). Na análise intragrupo foi identificado um aumento do TBARS apenas no grupo controle (antes=1,97±0,65; depois=2,28±0,47; p=0,049). Não foram evidenciadas modificações para as sulfidrilas e carbonilas nas análises intra e intergrupo. Conclusão: O efeito subagudo do exercício físico de baixa intensidade é capaz de modificar a resposta de peroxidação lipídica, não interferindo na peroxidação proteica e no fator antioxidante.

This study explored the effect of pterostilbene (PTS) complexed with hydroxypropyl-β-cyclodextrin (HPβCD) 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:HPβCD complex (corresponding to 25, 50, or 100 mg·kg−1of PTS) or vehicle (control group, CTR0) (an aqueous solution containing HPβCD; CTR0 and MCT0 (MCT group that did not receive PTS treatment)) via oral administration for 2 weeks. The results showed that the PTS:HPβCD 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:HPβCD 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-β-cyclodextrin could be a new therapeutic approach. Pterostilbene complexed with hydroxypropyl-β-cyclodextrin reestablishes redox homeostasis through glutathione metabolism modulation, leading to an improved MPI in pulmonary arterial hypertension-provoked right heart failure.

New findings What is the central question of this study? Does thyroid hormone treatment given after myocardial infarction preserve left ventricular function and treadmill exercise performance, and improve parameters of oxidative stress in the right ventricle and lungs of Wistar rats? What is the main finding and its importance? Thyroid hormone treatment improved the performance of the maximum exercise test in infarcted rats and induced effects in the heart and lungs that were similar to those observed with exercise training. This suggests there is a significant value of thyroid hormones for preserving exercise tolerance after myocardial infarction. Abstract Left ventricular myocardial infarction (MI) provokes damage in the heart and in other tissues, such as right ventricle and lungs. The present study elucidated whether thyroid hormone treatment (THT) may present positive effects in heart and lungs after MI, and whether or not these effects are similar to those of exercise training (ET). Male Wistar rats were divided into four groups: sham operated (SHAM), infarcted (MI), infarcted + exercise training (MIE), and infarcted + thyroid hormones (MIH). A maximum exercise test, left ventricle echocardiography, pulmonary histology, and oxidative stress in the right ventricle and lung were evaluated. THT and ET both reduced left ventricular dilatation and end-diastolic wall stress indexes to a similar extent. MI accentuated the content of macrophages and inflammatory infiltrate in the lungs, which was partially prevented in the MIH and MIE groups. THT and ET presented similar effects in the heart and lungs, and both improved the performance of the maximum exercise test in infarcted animals.

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.

Among the different cardiovascular disease complications, atherosclerosis-induced myocardial infarction (MI) is the major contributor of heart failure (HF) and loss of life. This review presents short- and long-term features of post-MI in human hearts and animal models. It is known that the heart does not regenerate, and thus loss of cardiac cells after an MI event is permanent. In survivors of a heart attack, multiple neurohumoral adjustments as well as simultaneous remodeling in both infarcted and noninfarcted regions of the heart help sustain pump function post-MI. In the early phase, migration of inflammatory cells to the infarcted area helps repair and remove the cell debris, while apoptosis results in the elimination of damaged cardiomyocytes, and there is an increase in the antioxidant response to protect the survived myocardium against oxidative stress (OS) injury. However, in the late phase, it appears that there is a relative increase in OS and activation of the innate inflammatory response in cardiomyocytes without any obvious inflammatory cells. In this late stage in survivors of MI, a progressive slow activation of these processes leads to apoptosis, fibrosis, cardiac dysfunction, and HF. Thus, this second phase of an increase in OS, innate inflammatory response, and apoptosis results in wall thinning, dilatation, and consequently HF. It is important to note that this inflammatory response appears to be innate to cardiomyocytes. Blunting of this innate immune cardiomyocyte response may offer new hope for the management of HF.

Ambrisentan (AMB) is an orphan drug approved for oral administration that has been developed for the treatment of pulmonary arterial hypertension (PAH), a chronic and progressive pathophysiological state that might result in death if left untreated. Lipid-core nanocapsules (LNCs) are versatile nanoformulations capable of loading lipophilic drugs for topical, vaginal, oral, intravenous, pulmonary, and nasal administration. Our hypothesis was to load AMB into these nanocapsules (LNCamb) and test their effect on slowing or reducing the progression of monocrotaline-induced PAH in a rat model, upon oral administration. LNCamb displayed a unimodal distribution of diameters (around 200 nm), negative zeta potential (–11.5 mV), high encapsulation efficiency (78%), spherical shape, and sustained drug release (50–60% in 24 h). The in vivo pharmacodynamic effect of the LNCamb group was evaluated by observing the echocardiography, hemodynamic, morphometric, and histological data, which showed a significant decrease in PAH in this group, as compared to the control group (AMBsolution). LNCamb showed the benefit of reversing systolic dysfunction and preventing vascular remodeling with greater efficacy than that observed in the control group. The originality and contribution of our work reveal the promising value of this nanoformulation as a novel therapeutic strategy for PAH treatment.

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.

In addition to being an antioxidant, thioredoxin (Trx) is known to stimulate signaling pathways involved in cell proliferation and to inhibit apoptosis. The aim of this study was to explore the role of Trx in some of these pathways along the progression of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Male rats were first divided into two groups: monocrotaline (MCT - 60 mg/kg i.p.) and control (received saline), that were further divided into three groups: 1, 2, and 3 weeks. Animals were submitted to echocardiographic analysis. Right and left ventricles were used for the measurement of hypertrophy, through morphometric and histological analysis. The lung was prepared for biochemical and molecular analysis. One week after MCT injection, there was an increase in thioredoxin reductase (TrxR) activity, a reduction in glutathione reductase (GR) activity, and an increase in Trx-1 and vitamin D3 up-regulated protein-1 (VDUP-1) expression. Two weeks after MCT injection, there was an increase in VDUP-1, Akt and cleaved caspase-3 activation, and a decrease in Trx-1 and Nrf2 expression. PAH-induced by MCT promoted a reduction in Nrf2 and Trx-1 expression as well as an increase in Akt and VDUP-1 expression after three weeks. The increase in pulmonary vascular resistance was accompanied by increased TrxR activity, suggesting an association between the Trx system and functional changes in the progression of PAH. It seems that Trx-1 activation was an adaptive response to MCT administration to cope with pulmonary remodeling and disease progression, suggesting a potential new target for PAH therapeutics.

Although a high cumulative dose of Doxorubicin (Dox) is known to cause cardiotoxicity, there is still a lack of understanding of the subcellular basis of this drug-induced cardiomyopathy. Differential effects of Dox on mitochondria and endoplasmic reticulum (ER) were examined in cardiomyocytes, tumor cells, implanted tumors and hearts of normal as well as tumor-bearing animals. Dox increased mitochondrial (Mito) Bax activation at 3 h in the cardiomyocyte without change in the DNA damage inducible transcriptor-3 (DDIT3) expression in the ER. Increased DDIT3 in these Dox-treated cardiomyocytes at 24 h suggested that increased MitoBax may have promoted ER stress related changes in DDIT3. Dissociation of immunoglobulin-binding protein (Bip) from activating transcription factor 6 (ATF6)-Bip complex in the ER was observed as an adaptive response to Dox. In contrast, breast cancer MCF7 cells showed an ER stress response to Dox with increased DDIT3 as early as 3 h which may have triggered a positive feedback activation of ATF6 at 12 and 24 h and promoted Calnexin. At these later time points, increased Bax activation in cancer cells suggested that MitoBax may be controlled by DDIT3 or by Calnexin. DDIT3 response in tumors was evoked by Dox, however this response was inversely correlated with increased Bip and Bax expression in hearts from tumor bearing animals. It is suggested that in Dox-induced cardiotoxicity both mitochondrial and ER stresses play an integral role through a mutual interaction where an inhibition of DDIT3 or Calnexin may also be crucial to achieve Dox resistance in cardiomyocytes.

Pterostilbene (PS), a natural and antioxidant polyphenolic compound emerges as a promising intervention in improving the myocardial infarction (MI) damages.This study aimed to evaluate PS actions in promoting redox homeostasis in lungs and right ventricle (RV) of infarcted animals.Male Wistar rats (60 day-old) were randomized into three groups: SHAM, MI (infarcted), and MI+PS (MI+pterostilbene). Seven days after MI procedure, rats were treated with PS (100 mg/kg/day) via gavage for eight days. Animals were euthanized and the lungs and RV were harvested for analyses of redox balance (Differences were considered significant when p0.05).Our results show that MI triggers a redox disruption scenario in RV and lungs, which can contribute to MI-induced damage on these organs. Consistently, PS mitigated oxidative stress and restored antioxidant defenses (GSH in lungs: SHAM= 0.79±0.07; MI=0.67±0.05; MI+PS=0.86±0.14; p0.05), indicating its protective role in this scenario.Our work evidences the PS potential use as an adjuvant therapeutic approach after MI focusing on protecting pulmonary and right-sided heart tissues.O pterostilbeno (PS), um composto polifenólico natural e antioxidante, surge como uma intervenção promissora para minimizar danos do infarto agudo do miocárdio (IAM).Este estudo teve como objetivo avaliar o desempenho do PS na promoção da homeostase redox nos pulmões e no ventrículo direito (VD) de animais infartados.Ratos Wistar machos (60 dias de idade) foram randomizados em três grupos: SHAM, IAM (infarto) e IAM+PS (IAM + pterostilbeno). Sete dias após o procedimento de IAM, os ratos foram tratados com PS (100 mg/kg/dia) por gavagem por oito dias. Os animais foram depois sacrificados e os pulmões e VD foram coletados para análise do balanço redox (diferenças foram consideradas significativas quando p0,05).Nossos resultados mostram que o IAM desencadeia a interrupção redox no VD e nos pulmões, o que pode contribuir para danos induzido pelo IAM nesses órgãos. Consistentemente, o PS mitigou o estresse oxidativo e restaurou as defesas antioxidantes (Glutationa – GSH nos pulmões: SHAM = 0,79 ± 0,07; IAM = 0,67 ± 0,05; IAM + PS = 0,86 ± 0,14; p0,05), indicando seu papel protetor neste cenário.Nosso trabalho evidencia o potencial do uso de PS como abordagem terapêutica adjuvante após IAM para proteção dos tecidos pulmonares e cardíacos direitos.

Context: Infarction leads to a decrease in NO bioavailability in the erythrocytes. Thyroid hormones (TH) present positive effects after infarction. However, there are no studies evaluating the effects of cardioprotective doses of TH in the erythrocytes after infarction.Objective: This study aimed to evaluate the effects of TH in NO bioavailability and oxidative stress parameters in the erythrocytes of infarcted rats.Material and methods: Wistar rats were allocated into the three groups: Sham-operated (SHAM), infarcted (AMI) and infarcted + TH (AMIT). AMIT rats received T4 and T3 for 12 days by gavage. Subsequently, the animals were evaluated by echocardiography and the LV and erythrocytes were collected.Results: TH improved NO bioavailability and increased catalase activity in the erythrocytes. Besides that, TH increased HIF-1α in the heart.Conclusion: TH seems to be positive for erythrocytes preventing a decrease in NO bioavailability and increasing antioxidant enzymatic defense after infarction.

The time-course of pulmonary arterial hypertension in the monocrotaline (MCT) model was investigated. Male rats were divided into two groups: MCT (received a 60 mg/kg i.p. injection) and control (received saline). The MCT and control groups were further divided into three cohorts, based on the follow-up interval: 1, 2, and 3 weeks. Right ventricle (RV) catheterization was performed and RV hypertrophy (RVH) was estimated. The lungs were used for biochemical, histological, molecular, and immunohistochemical analysis, while pulmonary artery rings were used for vascular reactivity. MCT promoted lung perivascular edema, inflammatory cells exudation, greater neutrophils and lymphocytes profile, and arteriolar wall thickness, compared to CTR group. Increases in pulmonary artery pressure and in RVH were observed in the MCT 2- and 3-week groups. The first week was marked by the presence of nitrosative stress (50% moderate and 33% accentuated staining by nitrotyrosine). These alterations lead to an adaptation of NO production by NO synthase activity after 2 weeks. Oxidative stress was evident in the third week, probably by an imbalance between endothelin-1 receptors, resulting in extracellular matrix remodeling, endothelial dysfunction, and RVH. Also, it was found a reduced pulmonary arterial vasodilatory response to acetylcholine after 2 (55%) and 3 (45%) weeks in MCT groups. The relevance of this study is precisely to show that nitrosative and oxidative stress predominate in distinct time windows of the disease progression.

The effects of exercise training on oxidative stress in gastrocnemius of rats with pulmonary hypertension were studied. Four groups were established: sedentary control (SC), sedentary monocrotaline (SM), trained control (TC), trained monocrotaline (TM). Exercise was applied for 4 weeks, 5 days/week, 50-60 min/session, at 60% of VO

Unhealthy lifestyle persistently feeds forward inflammation in metabolic organs thus imposing senescence-associated secretory phenotype (SASP), as observed in obesity and type 2 diabetes. However, SASP blocks physiological resolution of inflammation by suppressing the anti-inflammatory and anti-senescent heat shock (HS) response, i.e., the gene program centered in heat shock factor-1 (HSF1)-dependent expression heat shock proteins (HSPs). As SASP-inducing factors are not removed, leading to the perpetuation of inflammation, we argued that SIRT1-HSF1-HSP axis might also be suppressed in atherosclerosis, which could be reversible by heat treatment (HT), the most powerful HS response trigger. LDLr−/− adult mice were fed on high-fat/high-cholesterol diet from the age of 90 days until the end of study (age of 270 days). After 120 days under atherosclerotic diet, the animals were submitted to either whole-body HT (n = 42; 40 °C) or sham (n = 59; 37 °C) treatment (15 min/session), under anesthesia, once a week, for 8 weeks, being echographically and metabolically monitored. Aortic expressions of SIRT1, HSF1, HSP27, HSP72 and HSP73 were progressively depressed in atherosclerotic animals, as compared to normal (LDLr+/+; n = 25) healthy counterparts, which was paralleled by increased expression of NF-κB-dependent VCAM1 adhesion molecule. Conversely, HT completely reversed suppression of the above HS response proteins, while markedly inhibiting both VCAM1 expression and NF-κB DNA-binding activity. Also, HT dramatically reduced plasma levels of TG, total cholesterol, LDL-cholesterol, oxidative stress, fasting glucose and insulin resistance while rising HDL-cholesterol levels. HT also decreased body weight gain, visceral fat, cellular infiltration and aortic fatty streaks, and heart ventricular congestive hypertrophy, thereby improving aortic blood flow and myocardial performance (Tei) indices. Remarkably, heat-treated mice stopped dying after the third HT session (= 8 human years), suggesting a curative effect. Therefore, evolution of atherosclerosis is associated with suppression of the anti-inflammatory and anti-senescent SIRT1-HSF1-HSP molecular axis, which is refreshed by chronic heat treatment.

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.

This study was designed to investigate the effect of pterostilbene (PTS) on cardiac oxidative stress in vitro, as this is a simple and promising methodology to study cardiac disease. Cardiac myoblasts (H9c2 cells) and homogenised cardiac tissue were incubated with the PTS and cyclodextrin (PTS ? HPbCD) complex for 1 and 24 h, respectively, at concentrations of 50 lM for the cells and 25 and 50 lM for cardiac tissue. The PTS ? HPbCD complex was used to increase the solubility of PTS in water. After the pretreatment period, cardiomyoblasts were challenged with hydrogen peroxide (6.67 lM) for 10 min, while cardiac tissue was submitted to a hydroxyl radical generator system (30 min). Cellular viability, oxidative stress biomarkers (e.g. total reactive oxygen species (ROS), carbonyl assay and lipoperoxidation) and the antioxidant response (e.g. sulfhydryl and the antioxidant enzyme activities of superoxide dismutase, catalase and glutathione peroxidase) were evaluated. In cardiomyoblasts, the PTS ? HPbCD complex (50 lM) increased cellular viability. Moreover, the PTS ? HPbCD complex also significantly increased sulfhydryl levels in the cells submitted to an oxidative challenge. In cardiac tissue, lipid peroxidation, carbonyls and ROS levels were significantly increased in the groups submitted to oxidative damage, while the PTS ? HPbCD complex significantly reduced ROS levels in these groups. In addition, the PTS ? HPbCD complex also provoked increased catalase activity in both experimental protocols. These data suggest that the PTS ? HPbCD complex may play a cardioprotective role through a reduction of ROS levels associated with an improved antioxidant response.

Aortoiliac occlusive disease (AOD) and abdominal aortic aneurysm (AAA) are very important cardiovascular diseases that present different aspects of pathophysiology; however, oxidative stress and inflammatory response seem be relevant in both of them. Our objective was to evaluate oxidative damage and degree of inflammatory infiltrate in aortas of patients surgically treated for AOD and AAA.Levels of reactive oxygen species (ROS), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and myeloperoxidase (MPO) expression as well as nitrite levels and superoxide dismutase (SOD) and catalase (CAT) activities were evaluated in aortas of patients with AOD (n = 16) or AAA (n = 14), while the control group was formed by cadaveric organ donors (n = 10). We also analyzed the degree of inflammatory infiltrate in these aortas.There was an increase in ROS levels and NADPH oxidase activity in patients with AOD and AAA when compared with the control group, and the AOD group demonstrated higher ROS production and NADPH oxidase activity and also nitrite levels when compared with the AAA group (P 0.001). On the other hand, an increase of SOD activity in the AOD group and CAT activity in the AAA group was observed. Inflammatory infiltrate and MPO expression were higher in the AOD group when compared with the control group (P 0.05).Oxidative stress is relevant in both AOD and AAA, though AOD presented higher ROS levels and NADPH activity. Increased activities of antioxidant enzymes may be a compensatory phenomenon which occurs in aortas of patients with AOD and AAA. Perhaps, a relationship between oxidative stress and degree of inflammatory infiltrate may exist in the pathophysiology of AOD and AAA.

The objectives of this study were to promote the aqueous solubility of pterostilbene (PTS) by complexation with hydroxypropyl-β-cyclodextrin (HPβCD), characterize the complex under physical aspects, to make its oral administration feasible in biological tests, and to investigate their pharmacological properties. For 14 days, rats received daily PTS:HPΒCD complex at doses of 25, 50, or 100 mg kg−1 per day orally. The results showed no kidney or liver damage, nor any induction of apoptosis by the administered doses. Also, the complex showed dose-dependent antioxidant effects in the rat liver, as evidenced by a reduction in lipid peroxidation and reactive oxygen species, as well as an increase in non-enzymatic antioxidant. PTS:HPΒCD complex also increased the expression of sensitive redox proteins such as AKT and GSK-3β related to the insulin signaling pathway in the liver. Thus, the complexation demonstrated to be able to increase the apparent solubility of PTS making feasible dose curve administration and could be a food alternative complementary to antioxidant therapeutic. Therefore, the PTS:HPβCD complex can be used for prevention of diseases related to oxidative damage and insulin signaling.

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 24 h of SFN incubation. After 1 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 24 h than in those incubated for 1 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.

Background Pulmonary arterial hypertension is a disease characterized by increased pulmonary vascular resistance and redox imbalance, leading to failure of right ventricle. Trapidil has been described to improve the redox balance and cardiac conditions. Hypothesis Trapidil can improve the redox balance and contribute to functional improvements of the RV in PAH. Methods and Results Male, 5week-old Wistar rats were divided into four groups: Control, Control + Trapidil, Monocrotaline and Monocrotaline + Trapidil. PAH was induced by an intraperitoneal injection of monocrotaline 60 mg/kg at day 0. Treatment started at day 7 (5 or 8 mg/kg/day) until day 14, when animals were euthanized after echocardiography and catheterism. Right ventricular systolic pressure and pressure/time derivatives were increased in monocrotaline animals. The increased right ventricular diameters in monocrotaline groups were reduced with trapidil. Monocrotaline groups showed higher lipid peroxidation and glutathione peroxidase activity. Trapidil reduced NADPH oxidases activities and increased the reduced glutathiones/total glutathiones ratio. Protein expression of phospholamban in RV was diminished in monocrotaline groups, whereas expression of RyR and SERCA was enhanced in the groups treated with trapidil. Conclusion Our data suggest that trapidil induces an improvement in RV remodeling in PAH model, mitigating the progression of the disease.

This review addresses pulmonary arterial hypertension (PAH), an incurable disease, which determines high morbidity and mortality. Definition of the disease, its characteristics, classification, and epidemiology are discussed. A difficulty in the diagnosis of PAH due to the lack of symptoms specificity is highlighted. Echocardiographic analysis and electrocardiogram of patients help in the diagnosis and in the follow up of the disease. Nevertheless, right ventricle (RV) catheterization constitutes the gold standard for diagnosing PAH. Oxidative stress and inflammation, in an interactive manner, play a major role in the development of pulmonary vascular remodeling and consequent increase of pulmonary pressure. The latter results in an increase in RV afterload, culminating with RV hypertrophy, which may progress to failure. Both clinical and experimental studies have shown increased oxidative stress and inflammation, not only in lungs and pulmonary vasculature but also in RV. The use of experimental models, such as the monocrotaline-induced PAH, has helped in the understanding of the pathophysiology of PAH, as well as in the development of new therapeutic strategies. In addition to the traditional therapeutics, the use of therapeutic interventions capable of modulating oxidative stress and inflammation may offer newer strategies in the prevention as well as management of this disease.

The aim of this study was to investigate the role of the ß-adrenergic blocker bucindolol on endothelial dysfunction and pulmonary vascular remodeling in rats with pulmonary arterial hypertension (PAH). Male Wistar rats were divided into four groups: control, monocrotaline (MCT), control?+?bucindolol and monocrotaline?+?bucindolol (MCT?+?BCD). PAH was induced by an injection of monocrotaline (60?mg/kg i.p.). After two weeks, the animals were treated for seven days with bucindolol (2?mg/kg/day i.p.) or vehicle. Echocardiography was performed upon treatment completion to analyze pulmonary vascular resistance (PVR) and right ventricle (RV) myocardial performance index. Lungs were collected for oxidative stress and western blot analysis, and the pulmonary artery was analyzed for histological and immunohistochemical parameters. The MCT?+?BCD group showed a decrease (32%) in the protein expression of endothelin-1 type A receptor (ETAR) and in the ratio of ETA/endothelin-1 type B receptor (ETBR) (62%) as compared to the MCT group. Bucindolol treatment did not alter oxidative stress, as determined by lipid peroxidation analysis and antioxidant enzyme activities and expression, endothelial nitric oxide synthase immunocontent and decreased nitrotyrosine levels. Moreover, bucindolol improved vascular remodeling of the pulmonary artery in the MCT?+?BCD group by decreasing (21%) PVR and increasing RV workload in relation to MCT.