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Obesity is a major contributor to metabolic and cardiovascular disease. Although senescent cells have been shown to accumulate in adipose tissue, the role of senescence in obesity-induced metabolic disorders and in cardiac dysfunction is not yet clear; therefore, the therapeutic potential of managing senescence in obesity-related metabolic and cardiac disorders remains to be fully defined. We investigated the beneficial effects of a senolytic cocktail (dasatinib and quercetin) on senescence and its influence on obesity-related parameters. We found that the increase in body weight and adiposity, glucose intolerance, insulin resistance, dyslipidemia, hyperleptinemia, and hepatic disorders which were induced by an obesogenic diet were alleviated by senolytic cocktail treatment in mice. Treatment with senolytic compounds eliminated senescent cells, counteracting the activation of the senescence program and DNA damage in white adipose tissue (WAT) observed with an obesogenic diet. Moreover, the senolytic cocktail prevented the brown adipose tissue (BAT) whitening and increased the expression of the thermogenic gene profile in BAT and pWAT. In the hearts of obese mice, senolytic combination abolished myocardial maladaptation, reducing the senescence-associated secretory phenotype (SASP) and DNA damage, repressing cardiac hypertrophy, and improving diastolic dysfunction. Additionally, we showed that treatment with the senolytic cocktail corrected gene expression programs associated with fatty acid metabolism, oxidative phosphorylation, the P53 pathway, and DNA repair, which were all downregulated in obese mice. Collectively, these data suggest that a senolytic cocktail can prevent the activation of the senescence program in the heart and WAT and activate the thermogenic program in BAT. Our results suggest that targeting senescent cells may be a novel therapeutic strategy for alleviating obesity-related metabolic and cardiac disorders., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Cardiac hypertrophy (CH) is an adaptive response to maintain cardiac function; however, persistent stress responses lead to contractile dysfunction and heart failure. Although inflammation is involved in these processes, the mechanisms that control cardiac inflammation and hypertrophy still need to be clarified. The NLRP3 inflammasome is a cytosolic multiprotein complex that mediates IL-1β production. The priming step of NLRP3 is essential for increasing the expression of its components and occurs following NF-κB activation. Hyperthyroidism triggers CH, which can progress to maladaptive CH and even heart failure. We have shown in a previous study that thyroid hormone (TH)-induced CH is linked to the upregulation of S100A8, leading to NF-κB activation. Therefore, we aimed to investigate whether the NLRP3 inflammasome is involved in TH-induced CH and its potential role in CH pathophysiology. Hyperthyroidism was induced in NLRP3 knockout (NLRP3-KO), Caspase-1-KO and Wild Type (WT) male mice of the C57Bl/6J strain, aged 8-12 weeks, by triiodothyronine (7 μg/100 g BW, i.p.) administered daily for 14 days. Morphological and cardiac functional analysis besides molecular assays showed, for the first time, that TH-induced CH is accompanied by reduced NLRP3 expression in the heart and that it occurs independently of the NLRP3 inflammasome and caspase 1-related pathways. However, NLRP3 is important for the maintenance of basal cardiac function since NLRP3-KO mice had impaired diastolic function and reduced heart rate, ejection fraction, and fractional shortening compared with WT mice., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Previous studies show that COVID-19 survivors have elevated muscle sympathetic nerve activity (MSNA), endothelial dysfunction, and aortic stiffening. However, the neurovascular responses to mental stress and exercise are still unexplored. We hypothesized that COVID-19 survivors, compared with age- and body mass index (BMI)-matched control subjects, exhibit abnormal neurovascular responses to mental stress and physical exercise. Fifteen severe COVID-19 survivors (aged: 49 ± 2 yr, BMI: 30 ± 1 kg/m 2 ) and 15 well-matched control subjects (aged: 46 ± 3 yr, BMI: 29 ± 1 kg/m 2 ) were studied. MSNA (microneurography), forearm blood flow (FBF), and forearm vascular conductance (FVC, venous occlusion plethysmography), mean arterial pressure (MAP, Finometer), and heart rate (HR, ECG) were measured during a 3-min mental stress (Stroop Color-Word Test) and during a 3-min isometric handgrip exercise (30% of maximal voluntary contraction). During mental stress, MSNA (frequency and incidence) responses were higher in COVID-19 survivors than in controls ( P < 0.001), and FBF and FVC responses were attenuated ( P < 0.05). MAP was similar between the groups ( P > 0.05). In contrast, the MSNA (frequency and incidence) and FBF and FVC responses to handgrip exercise were similar between the groups ( P > 0.05). MAP was lower in COVID-19 survivors ( P < 0.05). COVID-19 survivors exhibit an exaggerated MSNA and blunted vasodilatory response to mental challenge compared with healthy adults. However, the neurovascular response to handgrip exercise is preserved in COVID-19 survivors. Overall, the abnormal neurovascular control in response to mental stress suggests that COVID-19 survivors may have an increased risk to cardiovascular events during mental challenge.

The objective of this systematic review was to examine the effects of exercise training on endothelial function in individuals with overweight and obesity. Our review study included only randomized controlled trials (RCTs) involving adults (≥ 18 years of age) with body mass index (BMI) ≥ 25.0 kg/m 2 . Our search was conducted in the electronic bases MEDLINE (PubMed), Cochrane, LILACS and EMBASE and in the gray literature. We performed random-effects analyses for effect estimates and used 95% prediction intervals (95% PI) for estimating the uncertainty of the study results. There were selected 10 RCTs involving 14 groups (n = 400). The quality assessment of studies using Cochrane risk-of-bias 2 (RoB 2) tool identified some concerns. Exercise training resulted in improved flow-mediated dilation (FMD) in individuals with overweight and obesity (p < 0.001) compared to the no-exercise control group. This effect of training modalities on FMD was seen for aerobic training (p < 0.001) but not for resistance training (p = 0.051). There was no difference in FMD in response to exercise training by BMI classification (overweight, obesity, overweight + obesity), p = 0.793. The present results are consistent with the notion that aerobic exercise training elicits favorable adaptations in endothelial function in individuals with overweight and obesity. Our findings should be interpreted with caution because of the small number of studies included in this review., (© 2023. The Author(s).)

Preserving vascular function is crucial for preventing multiorgan failure and death in ischemic and low-pressure states such as trauma/hemorrhagic shock (T/HS). It has recently been reported that inhibiting circulating proteases released from the bowel to the circulation during T/HS may preserve vascular function and improve outcomes following T/HS. This study aimed to evaluate the role of the serine protease inhibitor gabexate mesilate (GM) in preserving vascular function during T/HS when given enterally. We studied the vascular reactivity of mesenteric arteries from male Wistar rats treated with enteral GM (10 mg/kg) (GM-treated, n = 6) or control (Shock-control, n = 6) following (T/HS) using pressure myography. Concentration-response curves of endothelial-dependent and endothelial-independent agonists (e.g., acetylcholine, sodium nitroprusside) ranging from 10 -10 to 10 -5  M were performed. In a second set of experiments, ex-vivo arteries from healthy rats were perfused with plasma from shocked animals from both groups and vascular performance was similarly measured. Arteries from the GM-treated group demonstrated a preserved concentration-response curve to the α 1 adrenergic agonist phenylephrine compared to arteries from Shock-control animals (- logEC 50 : - 5.73 ± 0.25 vs. - 6.48 ± 0.2, Shock-control vs. GM-treated, p = 0.04). When perfused with plasma from GM-treated rats, healthy arteries exhibited an even greater constriction and sensitivity to phenylephrine (- logEC 50 : - 6.62 ± 0.21 vs. - 7.13 ± 0.21, Shock-control vs. GM-treated, p = 0.02). Enteral GM also preserved the endothelium-dependent vascular response to agonists following T/HS and limited syndecan-1 shedding as a marker of glycocalyx compromise (41.84 ± 9 vs. 17.63 ± 3.97 ng/mL, Shock-control vs. GM-treated, p = 0.02). Syndecan-1 cleavage was correlated with plasma trypsin-like activity (r 2  = 0.9611). Enteral gabexate mesilate was able to maintain vascular function in experimental T/HS, which was reflected by improved hemodynamics (mean arterial pressure 50.39 ± 7.91 vs. 64.95 ± 3.43 mmHg, Shock-control vs. GM treated, p = 0.0001). Enteral serine protease inhibition may be a potential therapeutic intervention in the treatment of T/HS., (© 2023. The Author(s).)

Background: COVID-19 has become a dramatic health problem during this century. In addition to high mortality rate, COVID-19 survivors are at increased risk for cardiovascular diseases 1-year after infection. Explanations for these manifestations are still unclear but can involve a constellation of biological alterations. We hypothesized that COVID-19 survivors compared with controls exhibit sympathetic overdrive, vascular dysfunction, cardiac morpho-functional changes, impaired exercise capacity, and increased oxidative stress., Methods: Nineteen severe COVID-19 survivors and 19 well-matched controls completed the study. Muscle sympathetic nerve activity (microneurography), brachial artery flow-mediated dilation and blood flow (Doppler-Ultrasound), carotid-femoral pulse wave velocity (Complior), cardiac morpho-functional parameters (echocardiography), peak oxygen uptake (cardiopulmonary exercise testing), and oxidative stress were measured ~3 months after hospital discharge. Complementary experiments were conducted on human umbilical vein endothelial cells cultured with plasma samples from subjects., Results: Muscle sympathetic nerve activity and carotid-femoral pulse wave velocity were greater and brachial artery flow-mediated dilation, brachial artery blood flow, E/e' ratio, and peak oxygen uptake were lower in COVID-19 survivors than in controls. COVID-19 survivors had lower circulating antioxidant markers compared with controls, but there were no differences in plasma-treated human umbilical vein endothelial cells nitric oxide production and reactive oxygen species bioactivity. Diminished peak oxygen uptake was associated with sympathetic overdrive, vascular dysfunction, and reduced diastolic function in COVID-19 survivors., Conclusions: Our study revealed that COVID-19 survivors have sympathetic overactivation, vascular dysfunction, cardiac morpho-functional changes, and reduced exercise capacity. These findings indicate the need for further investigation to determine whether these manifestations are persistent longer-term and their impact on the cardiovascular health of COVID-19 survivors.

Cardiovascular diseases are the main cause of death worldwide. Recent studies have revealed the influence of histone-modifying enzymes in cardiac remodeling and heart dysfunction. The Set7 methyltransferase regulates the expression of several genes through the methylation of histones and modulates the activity of non-histone proteins. However, the role of Set7 in cardiac remodeling and heart dysfunction remains unknown. To address this question, wild-type (WT) and Set7 knockout (KO) male mice were injected with isoproterenol or saline. WT mice injected with isoproterenol displayed a decrease in Set7 activity in the heart. In addition, WT and Set7 KO mice injected with isoproterenol exhibited cardiac hypertrophy. Interestingly, Set7 deletion exacerbated cardiac hypertrophy in response to isoproterenol but attenuated myocardial fibrosis. Echocardiograms revealed that WT mice injected with isoproterenol had lowered ejection fractions and fractional shortening, and increased E'-wave deceleration time and E/A ratio compared with their controls. Conversely, Set7 KO mice did not show alteration in these parameters in response to isoproterenol. However, prolonged exposure to isoproterenol induced cardiac dysfunction both in WT and Set7 KO mice. Both isoproterenol and Set7 deletion changed the transcriptional profile of the heart. Moreover, Set7 deletion increased the expression of Pgc1α and mitochondrial DNA content in the heart, and reduced the expression of cellular senescence and inflammation markers in response to isoproterenol. Taken together, our data suggest that Set7 deletion attenuates isoproterenol-induced myocardial fibrosis and delays heart dysfunction, suggesting that Set7 plays an important role in cardiac remodeling and dysfunction in response to stress., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Cardiac rehabilitation with aerobic exercises is the first strategy for nonpharmacological treatment in the postoperative period of individuals undergoing coronary artery bypass grafting (CABG) to improve functional capacity and vascular health. However, other exercise modalities remain uncertain regarding the same benefits. Objectives: Evaluation of the effect of different modalities of exercise, such as early cardiac rehabilitation on subjects submitted to CABG in the six-minute walk test (6-MWT) and on the percentage of flow-mediated dilatation (FMD) of the brachial artery. Methods: A randomized clinical trial in which 15 patients (62.7 ± 6.7 years) who underwent CABG were randomly assigned to the following groups: isometric (IG, Handgrip Jamar®), ventilatory muscle training (VG, PowerBreathe®) and control (CG, conventional respiratory and motor physiotherapy). All patients were attended to physically twice a day (20 min/session) for a consecutive week after the CABG (hospital admission). Functional capacity was assessed by 6-MWT and endothelial function was assessed through the technique of FMD, before and after (~7 days) admission to CABG. The doppler ultrasound videos were analyzed by Cardiovascular Suite® software (Quipu, Pisa, Italy) to measure %FMD. Statistics: Generalized estimation equation, followed by Bonferroni post hoc (p < 0.05). Results: Systolic, diastolic and mean arterial pressure (SBP/DBP/MAP, respectively) were 133, 76 and 95 mmHg. The groups presented walking meters (m) distance before and after intervention of: IGbasal 357.80 ± 47.15 m vs. IGpost 306.20 ± 61.63 m, p = 0.401 (+51 m); VGbasal 261.50 ± 19.91 m vs. VGpost 300.75 ± 26.29 m, p = 0.052 (+39 m); CG basal 487.83 ± 83.23 m vs. CGpost 318.00 ± 31.08, p = 0.006 (−169 m). %FMD before and after intervention was IGbasal 10.4 ± 4.8% vs. IGpost 2.8 ± 2.5%, p = 0.152; VGbasal 9.8 ± 5.1% vs. VGpost 11.0 ± 6.1%, p = 0.825; CGbasal 9.2 ± 15.8% vs. CGpost 2.7 ± 2.6%, p = 0.710 and resting mean basal blood flow was IGbasal 162.0 ± 55.0 mL/min vs. IGpost 129.9 ± 63.7 mL/min, p = 0.662; VGbasal 83.74 ± 12.4 mL/min vs. VGpost 58.7 ± 17.1 mL/min, p = 0.041; CGbasal 375.6 ± 183.7 mL/min vs. CGpost 192.8 ± 115.0 mL/min, p = 0.459. Conclusions: Ventilatory muscle training for early cardiac rehabilitation improved acute functional capacity and modulated mean flow of individuals undergoing CABG.

Doxorubicin (DOX) is an anthracycline antibiotic that exhibits high heart toxicity. Human-induced pluripotent stem cell-derived ventricular cardiomyocytes (hiPSC-vCMs) are important in vitro models for testing drug cardiotoxicity. Photobiomodulation therapy (PBMT) is a non-invasive therapy that stimulates cells growth and self-repair using light irradiation. This study aimed to investigate the in vitro effects of PBMT preconditioning on cardiotoxicity induced by DOX. HiPSC-vCMs were treated with PBMT for 500 s, followed by the addition of 2 μM DOX. LED irradiation preconditioning parameters were at 660 nm with an irradiance of 10 mW/cm 2 , performing 5 J/cm 2 , followed by 24-h DOX exposure (2 μM). Human iPSC-vCMs treated with 2 μM DOX or irradiated with PBMT composed the second and third groups, respectively. The control group did neither receive PBMT preconditioning nor DOX and was irradiated with a white standard lamp. Cells from all groups were collected to perform mRNA and miRNA expressions quantification. PBMT, when applied before the DOX challenge, restored the viability of hiPSC-vCMs and reduced ROS levels. Although downregulated by DOX, myocardial UCP2 mRNA expression presented marked upregulation after PBMT preconditioning. Expression of eNOS and UCP2 mRNA and NO production were decreased after DOX exposure, and PBMT preconditioning before the DOX challenge reversed these changes. Moreover, our data indicated that PBMT preconditioning lowered the miR-24 expression. Our data suggested that PBMT preconditioning ameliorated in vitro DOX-induced cardiotoxicity on transcription level, restoring NO levels and reducing oxidative stress., (© 2021. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Aims: Both postprandial lipemia (PPL) and disturbed blood flow (DBF) induce endothelial dysfunction. However, the interactive effect of these stimuli on endothelial function is currently unknown. In the present study, we tested whether PPL plus DBF causes a greater reduction in flow-mediated dilation (FMD) than PPL and if this response is associated with elevations in oxidative stress and endothelial microvesicles (EMVs)., Methods: Eighteen individuals (aged 28 ± 1yrs, 3 females, and BMI 24.43 ± 0.8kg/m 2 ) randomly underwent two experimental sessions: PPL and PPL plus DBF. FMD and venous blood samples were obtained at baseline and 30, 70, and 110 min after stimulation. PPL was induced by fat overload via mozzarella pizza ingestion and DBF by forearm cuff inflation to 75 mm Hg per 30 min. Lipidic profile, oxidative stress (thiobarbituric acid reactive substances, TBARS; ferric reducing/antioxidant power, FRAP; hydrogen peroxide, H 2 O 2 ) and EMVs were measured in blood samples., Results: Hypertriglyceridemia was observed in both sessions. Retrograde shear rate and oscillatory index responses were significantly higher in the PPL plus DBF compared with PPL. PPL plus DBF evoked a greater reduction in FMD than did PPL and EMVs, NADPH oxidase, and H 2 O 2 similarly increased in both sessions, but TBARS and FRAP did not change., Conclusion: These data indicate that the association of PPL plus DBF additively impairs endothelium-dependent function in 110 min after stimulus in healthy individuals, despite a similar increase in oxidative stress and EMVs. Further studies are needed to understand the mechanisms associated with the induced-endothelial dysfunction by association of PPL and DBF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Araujo, Silva, Guerra, Izaias, Rocha, Faria, Rocha, Dalmazo, Araujo, Marciano Consolim-Colombo, de Angelis, Irigoyen and Sales.)

Background: Arterial hypertension has a direct association with endothelial dysfunction and major cardiovascular events. There is evidence showing the benefits of aerobic exercise on flow-mediated dilation (FMD) in hypertensive individuals but little is known about the effect of autonomic nervous system (ANS) activation on FMD of the brachial artery in response to different types of exercise in this specific population. This study aims to examine the effects of ANS activation on FMD of the brachial artery in response to exercise in hypertensive individuals following a session of different types of exercise including aerobic exercise (AE), resistance exercise (RE), or combined exercise (CE)., Methods: Thirty-nine hypertensive volunteers aged 35 to 55 years will be randomly assigned to two exercise sessions: AE (40 min on a cycle ergometer at 60% of HR reserve), RE (4 lower limb sets with 12 repetitions at 60% 1-RM for 40 min), or CE (RE for 20 min + AE for 20 min). Each exercise group will be randomized to receive either an α1-adrenergic blocker (doxazosin 0.05 mg/kg -1 ) or placebo. Ultrasound measurement of FMD is performed 10 min before and 10, 40, and 70 min after exercise. ANS activation is monitored using a Finometer and measurements are taken during 10 min before each FMD assessment. Arterial stiffness is assessed by pulse wave velocity (PWV) analysis using a Complior device., Discussion: We expect to demonstrate the effect of ANS activation on FMD of the brachial artery in hypertensive individuals in response to different types of exercise. This study may give some insight on how to improve exercise prescription for hypertension management., Trial Registration: https://clinicaltrials.gov and ID "NCT04371757". Registered on May 1, 2020., (© 2021. The Author(s).)

Mechanisms involved in the acute responses to renal denervation (RDN) have yet to be fully understood. We assessed urinary volume, autonomic control and aorta vascular reactivity after acute RDN. Male normotensive Wistar rats and spontaneously hypertensive rats (SHR) were divided into normotensive + RDN (ND) or sham surgery (NS), and hypertensive + RDN (HD) or sham surgery (HS). Metabolic parameters and hemodynamic measurements were recorded 72h and 4 days after intervention, respectively. Aortic rings were studied 7 days post RDN in an isometric myograph. Concentration-response curves to phenylephrine, sodium nitroprusside and acetylcholine (10 -10 -10 -5  M) were performed. Two-way ANOVA was used for group comparisons and differences reported when p < 0.05. Results are presented as mean ± SEM. Urinary volume was 112% higher in HD vs. HS (HS = 14.94 ± 2.5 mL; HD = 31.69 ± 2.2 mL) and remained unchanged in normotensive rats. Systolic BP was lower in HD rats (HS = 201 ± 12 vs. HD = 172 ± 3 mmHg) without changes in normotensive group. HD group showed increased HF and LF modulation (HS = 5.8 ± 0.7 ms 2 vs. HD = 13.4 ± 1.4 ms 2 ; HS = 3.5 ± 0.7 ms 2 vs. HD = 10.5 ± 1.7 ms 2 , respectively). RDN normalized vascular reactivity in HD rats and increased phenylephrine response in ND rats. Acute fall in BP induced by RDN is associated with increased urinary volume, which in turn may also have contributed to functional changes of the aorta.

Background: Patients with rheumatoid arthritis spend most of their daily hours in sedentary behavior (sitting), a predisposing factor to poor health-related outcomes and all-cause mortality. Interventions focused on reducing sedentary time could be of novel therapeutic relevance. However, studies addressing this topic remain scarce. We aim to investigate the feasibility and efficacy of a newly developed intervention focused on reducing sedentary time, and potential clinical, physiological, metabolic and molecular effects in rheumatoid arthritis., Methods: The Take a STAND for Health study is a 4-month, parallel-group, randomized controlled trial, in which postmenopausal patients with rheumatoid arthritis will set individually tailored, progressive goals to replace their sedentary time with standing and light-intensity activities. Patients will be recruited from the Clinical Hospital (School of Medicine, University of Sao Paulo) and will be assessed at baseline and after a 4-month follow up. Outcomes will include objectively measured sedentary behavior (primary outcome) and physical activity levels, clinical parameters, anthropometric parameters and body composition; aerobic fitness, muscle function, blood pressure, cardiovascular autonomic function, vascular function and structure, health-related quality of life, and food intake. Blood and muscle samples will be collected for assessing potential mechanisms, through targeted and non-targeted approaches., Discussion: Findings will be of scientific and clinical relevance with the potential to inform new prescriptions focused on reducing sedentary behavior, a modifiable risk factor that thus far has been overlooked in patients with rheumatoid arthritis., Trial Registration: ClinicalTrials.gov, NCT03186924. Registered on 14 June 2017.

To retrieve and assess the available data in the literature about the safety and efficacy of baroreflex activation therapy (BAT) in heart failure with reduced ejection fraction (HFrEF) patients, through a rapid systematic review of clinical studies. Rapid systematic review of literature. Searched electronic databases included PubMed, EMBASE, CENTRAL, Scopus, and Web of Science using Mesh and free terms for heart failure and BAT. No language restriction was used for the searches. We included full peer reviewed publications of clinical studies (randomized or not), including patients with HFrEF undergoing BAT, with or without control group, assessing safety and efficacy outcomes. One reviewer conducted the analysis of the selected abstracts and the full-text articles, performed data extraction, and evaluated the methodological quality of the selected articles. The methodological quality was assessed according to the Cochrane Collaboration instruments. A descriptive summary of the results is provided. Of the 441 citations screened, 10 publications were included (three were only conference abstracts), reporting data from three studies. Only one study was a randomized clinical trial. Two studies reported a 6 month following, and the other study analysed outcomes up to 41 months. The procedure seems to be safe when performed by a well-trained multi-professional team. An 86% rate of system and procedure-related complication-free was reported, with no cranial nerve injuries. Improvements in New York Heart Association class of heart failure, quality of life, 6 min walk test, and hospitalization rates, as well as in muscle sympathetic nerve activity. No meta-analysis was conducted because of the lack of homogeneity across studies; the results from each study are reported individually. BAT procedure seems to be safe if appropriate training is provided. Improvements in clinical outcomes were described in all included studies. However, several limitations do not allow us to make conclusive statements on the efficacy of BAT for HFrEF. New well-designed trials are still needed., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: The renin-angiotensin system (RAS) plays an important role in the pathophysiology of vascular diseases, especially as a mediator of inflammation and tissue remodelling. Alamandine (Ala 1 -angiotensin-(1-7)) is a new biologically active peptide from the RAS, interacting with Mas-related G-protein-coupled receptor member D. Although a growing number of studies reveal the cardioprotective effects of alamandine, there is a paucity of data on its participation in vascular remodelling associated events. In the present study, we investigated the effects of alamandine on ascending aorta remodelling after transverse aortic constriction (TAC) in mice. Methods and results: C57BL/6J male mice were divided into the following groups: Sham (sham-operated), TAC (operated) and TAC+ALA (operated and treated with alamandine-HPβCD (2-Hydroxypropyl-β-cyclodextrin), 30 μg/kg/day, by gavage). Oral administration of alamandine for 14 days attenuated arterial remodelling by decreasing ascending aorta media layer thickness and the cells density in the adventitia induced by TAC. Alamandine administration attenuated ascending aorta fibrosis induced by TAC, through a reduction in the following parameters; total collagen deposition, expression collagen III and transforming growth factor-β (TGF-β) transcripts, matrix metalloproteinases (MMPs) activity and vascular expression of MMP-2. Importantly, alamandine decreased vascular expression of proinflammatory genes as CCL2 , tumour necrosis factor α ( TNF-α ) and interleukin-1β ( IL-1β ), and was able to increase expression of MRC1 and FIZZ1, pro-resolution markers, after TAC surgery. Conclusion: Alamandine treatment attenuates vascular remodelling after TAC, at least in part, through anti-fibrotic and anti-inflammatory effects. Hence, this work opens new avenues for the use of this heptapeptide also as a therapeutic target for vascular disease., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Exercise training and pharmacological treatments are important strategies to minimize the deleterious effects of MI. However, little is known about the effects of resistance training combined with pyridostigmine bromide (PYR) treatment on cardiac and autonomic function, as well as on the inflammatory profile after MI. Thus, in the present study, male Wistar rats were randomly assigned into: control (Cont); sedentary infarcted (Inf); PYR - treated sedentary infarcted rats (Inf+P); infarcted rats undergoing resistance exercise training (Inf+RT); and infarcted rats undergoing PYR treatment plus resistance training (Inf+RT+P). After 12 weeks of resistance training (15-20 climbs per session, with a 1-min rest between each climb, at a low to moderate intensity, 5 days a week) and/or PYR treatment (0.14 mg/mL of drink water), hemodynamic function, autonomic modulation, and cytokine expressions were evaluated. We observed that 3 months of PYR treatment, either alone or in combination with exercise, can improve the deleterious effects of MI on left ventricle dimensions and function, baroreflex sensitivity, and autonomic parameters, as well as systemic and tissue inflammatory profile. Furthermore, additional benefits in a maximal load test and anti-inflammatory state of skeletal muscle were found when resistance training was combined with PYR treatment. Thus, our findings suggest that the combination of resistance training and PYR may be a good therapeutic strategy since they promote additional benefits on skeletal muscle anti-inflammatory profile after MI.

We previously reported that cholinergic stimulation with pyridostigmine (PY) induces anti-inflammatory cell recruitment soon after myocardial infarction (MI). In this study, we evaluated the anti-inflammatory effects of PY during the proliferative phase of cardiac repair by analyzing the infiltration of macrophages, Treg lymphocytes, oxidative stress and inflammatory cytokines. Wistar rats underwent control sham surgery or ligation of the left coronary artery and were randomly allocated to remain untreated (untreated infarcted group, I) or to receive PY (30 mg·kg(-1)·day(-1)) in the supplied water (infarcted treated group, I + PY). Blood pressure and heart rate variability were registered at day 5 post-MI. The animals were euthanized 7 days after thoracotomy, when the hearts were removed and processed for immunohistochemistry (CD68, CD206, FOXP3), cytokines (IL-1β, IL-6, IL-10, TNF-α) and oxidative stress (superoxide dismutase, catalase, glutathione peroxidase, lipidic and protein peroxidation). PY treatment increased parasympathetic modulation, M2 macrophages and the anti-oxidant enzyme activity but reduced protein oxidation (carbonyls) and the concentration of IL-1β, IL-6, TNF-α and IL-10. Cholinergic stimulation induces parasympathetic neuro-immune modulation and anti-inflammatory cell enrollment as well as prevents oxidative stress and cytokine production after MI.

Objective: To investigate the effects of acute and chronic exercise in female patients with remissive Takayasu arteritis (TAK)., Methods: This was a 2-part prospective study. In study 1, cytokines and soluble tumor necrosis factor (TNF) receptors were assessed at rest and every 60 minutes during a 3-hour recovery period following an acute exercise session in TAK (n = 11) and heathy control (n = 10) groups. In study 2, a subsample from the TAK group (n = 6) underwent a 12-week exercise training program. Before and after training, the acute session of aerobic exercise was performed and cytokines and soluble TNF receptors were assessed at the same time points described above. Muscle function, strength, aerobic capacity, endothelial function, quality of life, and walking impairment scores were evaluated., Results: In study 1, the acute session of aerobic exercise led to overall similar responses on cytokine kinetics in the TAK and heathy control groups. In study 2, the exercise training program did not exacerbate inflammatory cytokines in TAK patients, while the proinflammatory cytokine TNF was diminished both at rest and following the acute session of aerobic exercise. In addition, the exercise training program increased the pro-angiogenic factors vascular endothelial growth factor (at rest) and platelet-derived growth factor AA (at rest and in response to the acute session of aerobic exercise). The exercise training program improved muscle strength and function, whereas aerobic capacity, quality of life, and endothelial function parameters remained unchanged., Conclusion: Exercise could be a well-tolerated, safe, and effective intervention able to induce immunomodulatory and pro-angiogenic effects and to increase strength and function in patients with TAK., (© 2016, American College of Rheumatology.)