45 results on '"Motta-Santos D"'
Search Results
2. Neprilysin is a mediator of alternative renin-angiotensin-system activation in the murine and human kidney
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Domenig, O., Manzel, A., Grobe, N., Königshausen, E., Kaltenecker, C.C., Kovarik, J.J., Stegbauer, J., Gurley, S.B., van Oyen, D., Antlanger, M., Bader, M., Motta-Santos, D., Santos, R.A., Elased, K.M., Säemann, M.D., Linker, R.A., and Poglitsch, M.
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Cardiovascular and Metabolic Diseases ,fungi ,hormones, hormone substitutes, and hormone antagonists - Abstract
Cardiovascular and renal pathologies are frequently associated with an activated renin-angiotensin-system (RAS) and increased levels of its main effector and vasoconstrictor hormone angiotensin II (Ang II). Angiotensin-converting-enzyme-2 (ACE2) has been described as a crucial enzymatic player in shifting the RAS towards its so-called alternative vasodilative and reno-protective axis by enzymatically converting Ang II to angiotensin-(1-7) (Ang-(1-7)). Yet, the relative contribution of ACE2 to Ang-(1-7) formation in vivo has not been elucidated. Mass spectrometry based quantification of angiotensin metabolites in the kidney and plasma of ACE2 KO mice surprisingly revealed an increase in Ang-(1-7), suggesting additional pathways to be responsible for alternative RAS activation in vivo. Following assessment of angiotensin metabolism in kidney homogenates, we identified neprilysin (NEP) to be a major source of renal Ang-(1-7) in mice and humans. These findings were supported by MALDI imaging, showing NEP mediated Ang-(1-7) formation in whole kidney cryo-sections in mice. Finally, pharmacologic inhibition of NEP resulted in strongly decreased Ang-(1-7) levels in murine kidneys. This unexpected new role of NEP may have implications for the combination therapy with NEP-inhibitors and angiotensin-receptor-blockade, which has been shown being a promising therapeutic approach for heart failure therapy.
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- 2016
3. Angiotensin-(1-7) infusion in COVID-19 patients admitted to the ICU: a seamless phase 1-2 randomized clinical trial.
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Martins ALV, Annoni F, da Silva FA, Bolais-Ramos L, de Oliveira GC, Ribeiro RC, Diniz MML, Silva TGF, Pinheiro BD, Rodrigues NA, Dos Santos Matos AH, Motta-Santos D, Campagnole-Santos MJ, Verano-Braga T, Taccone FS, and Santos RAS
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Background: The coronavirus-related disease (COVID-19) is mainly characterized by a respiratory involvement. The renin-angiotensin system (RAS) has a relevant role in the pathogenesis of COVID-19, as the virus enters host's cells via the angiotensin-converting enzyme 2 (ACE2)., Methods: This investigator-initiated, seamless phase 1-2 randomized clinical trial was conceived to test the safety and efficacy of continuous short-term (up to 7 days) intravenous administration of Angiotensin-(1-7) in COVID-19 patients admitted to two intensive care units (ICU). In addition to standard of care, intravenous administration of Angiotensin-(1-7) was started at 5 mcg/Kg day and increased to 10 mcg/Kg day after 24 h (Phase 1; open label trial) or given at 10 mcg/Kg day and continued for a maximum of 7 days or until ICU discharge (Phase 2; double-blind randomized controlled trial). The rate of serious adverse events (SAEs) served as the primary outcome of the study for Phase 1, and the number of oxygen free days (OFDs) by day 28 for Phase 2., Results: Between August 2020 and July 2021, when the study was prematurely stopped due to low recruitment rate, 28 patients were included in Phase 1 and 79 patients in Phase 2. Of those, 78 were included in the intention to treat analysis, and the primary outcome was available for 77 patients. During Phase 1, one SAE (i.e., bradycardia) was considered possibly related to the infusion, justifying its discontinuation. In Phase 2, OFDs did not differ between groups (median 19 [0-21] vs. 14 [0-18] days; p = 0.15). When patients from both phases were analyzed in a pooled intention to treat approach (Phase 1-2 trial), OFDs were significantly higher in treated patients, when compared to controls (19 [0-21] vs. 14 [0-18] days; absolute difference -5 days, 95% CI [0-7] p = 0.04)., Conclusions: The main findings of our study indicate that continuous intravenous infusion of Angiotensin-(1-7) at 10 mcg/Kg day in COVID-19 patients admitted to the ICU with severe pneumonia is safe. In Phase II intention to treat analysis, there was no significant difference in OFD between groups. Trial Registration ClinicalTrials.gov Identifier: NCT04633772-Registro Brasileiro de Ensaios Clínicos, UTN number: U1111-1255-7167., (© 2024. The Author(s).)
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- 2024
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4. Effects of gallic acid and physical training on liver damage, force, and anxiety in obese mice: Hepatic modulation of Sestrin 2 (SESN2) and PGC-α expression.
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Sousa JN, Sousa BVO, Santos EPD, Ribeiro GHM, Pereira APM, Guimarães VHD, Queiroz LDRP, Motta-Santos D, Farias LC, Guimarães ALS, de Paula AMB, and Santos SHS
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- Animals, Mice, Male, Anxiety drug therapy, Nuclear Proteins metabolism, Nuclear Proteins genetics, Diet, High-Fat adverse effects, Gene Expression Regulation drug effects, Sestrins, Gallic Acid pharmacology, Physical Conditioning, Animal, Liver metabolism, Liver drug effects, Obesity metabolism, Obesity genetics, Obesity drug therapy, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha genetics, Mice, Obese
- Abstract
Obesity and overweight are multifactorial diseases affecting more than one-third of the world's population. Physical inactivity contributes to a positive energy balance and the onset of obesity. Exercise combined with a balanced diet is an effective non-pharmacological strategy to improve obesity-related disorders. Gallic acid (GA), is a natural endogenous polyphenol found in a variety of fruits, vegetables, and wines, with beneficial effects on energetic homeostasis. The present study aims to investigate the effects of exercise training on obese mice supplemented with GA. Animal experimentation was performed with male Swiss mice divided into five groups: ST (standard control), HFD (obese control), HFD + GA (GA supplement), HFD + Trained (training), and HFD + GA + Trained (GA and training). The groups are treated for eight weeks with 200 mg/kg/body weight of the feed compound and, if applicable, physical training. The main findings of the present study show that GA supplementation improves liver fat, body weight, adiposity, and plasma insulin levels. In addition, animals treated with the GA and a physical training program demonstrate reduced levels of anxiety. Gene expression analyses show that Sesn2 is activated via PGC-1α independent of the GATOR2 protein, which is activated by GA in the context of physical activity. These data are corroborated by molecular docking analysis, demonstrating the interaction of GA with GATOR2. The present study contributes to understanding the metabolic effects of GA and physical training and demonstrates a new hepatic mechanism of action via Sestrin 2 and PGC-1α., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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5. Effects of oral HPΒCD-angiotensin-(1-7) supplementation on recreational mountain bike athletes: a crossover study.
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Silva de Moura S, de Assis Dias Martins-Júnior F, Cruz de Oliveira E, Coelho DB, Boari D, Lima-Silva AE, Motta-Santos D, Augusto Souza Dos Santos R, and Becker LK
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- Humans, Male, Cross-Over Studies, 2-Hydroxypropyl-beta-cyclodextrin, Bicycling physiology, Blood Glucose, Lactates, Dietary Supplements, Athletes, Fatigue, Nitrites, Athletic Performance, Angiotensin I, Peptide Fragments
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Background: Supplementation with Angiotensin-(1-7) [(Ang-1-7)] has received considerable attention due to its possible ergogenic effects on physical performance. The effects of a single dose of Ang-(1-7) on the performance of mountain bike (MTB) athletes during progressive load tests performed until the onset of voluntary fatigue have previously been demonstrated. This study tested the effects of Ang-(1-7) in two different exercise protocols with different metabolic demands: aerobic (time trial) and anaerobic (repeated sprint)., Methods: Twenty one male recreational athletes were given capsules containing an oral formulation of HPβCD-Ang-(1-7) (0.8 mg) and HPβCD-placebo (only HPβCD) over a 7-day interval; a double-blind randomized crossover design was used. Physical performance was examined using two protocols: a 20-km cycling time trial or 4 × 30-s repeated all-out sprints on a leg cycle ergometer. Data were collected before and after physical tests to assess fatigue parameters, and included lactate levels, and muscle activation during the sprint protocol as evaluated by electromyography (EMG); cardiovascular parameters: diastolic and systolic blood pressure and heart rate; and performance parameters, time to complete (time trial), maximum power and mean power (repeated sprint)., Results: Supplementation with an oral formulation of HPβCD-Ang-(1-7) reduced basal plasma lactate levels and promoted the maintenance of plasma glucose levels after repeated sprints. Supplementation with HPβCD-Ang-(1-7) also increased baseline plasma nitrite levels and reduced resting diastolic blood pressure in a time trial protocol. HPβCD-Ang-(1-7) had no effect on the time trial or repeat sprint performance, or on the EMG recordings of the vastus lateralis and vastus medialis., Conclusions: Supplementation with HPβCD-Ang-(1-7) did not improve physical performance in time trial or in repeated sprints; however, it promoted the maintenance of plasma glucose and lactate levels after the sprint protocol and at rest, respectively. In addition, HPβCD-Ang-(1-7) also increased resting plasma nitrite levels and reduced diastolic blood pressure in the time trial protocol., Trial Registration: RBR-2nbmpbc, registered January 6th, 2023. The study was prospectively registered.
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- 2024
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6. Scale up of implementation of a multidimensional intervention to enhance hypertension and diabetes care at the primary care setting: A protocol for a cluster-randomized study in Brazil.
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Fonseca SF, Ribeiro ALP, Cimini CCR, Soares TBC, Delfino-Pereira P, Nogueira LT, Moura RMF, Motta-Santos D, Ribeiro LB, Camargos MCS, Paixão MC, Pires MC, Batchelor J, and Marcolino MS
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- Humans, Adolescent, Brazil epidemiology, Delivery of Health Care, Primary Health Care methods, Randomized Controlled Trials as Topic, Hypertension drug therapy, Diabetes Mellitus epidemiology, Diabetes Mellitus therapy
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Background: Hypertension and diabetes mellitus (DM) are highly prevalent in low and middle-income countries (LMICs), and the proportion of patients with uncontrolled diseases is higher than in high-income countries. Innovative strategies are required to surpass barriers of low sources, distance and quality of health care. Our aim is to assess the uptake and effectiveness of the implementation of an integrated multidimensional strategy in the primary care setting, for the management of people with hypertension and diabetes mellitus in Brazil., Methods: This scale up implementation study called Control of Hypertension and diAbetes in MINas Gerais (CHArMING) Project has mixed-methods, and comprehends 4 steps: (1) needs assessment, including a standardized structured questionnaire and focus groups with health care practitioners; (2) baseline period, 3 months before the implementation of the intervention; (3) cluster randomized controlled trial (RCT) with a 12-months follow-up period; and (4) a qualitative study after the end of follow-up. The cluster RCT will randomize 35 centers to intervention (n = 18) or usual care (n = 17). Patients ≥18 years old, with diagnosis of hypertension and/or DM, of 5 Brazilian cities in a resource-constrained area will be enrolled. The intervention consists of a multifaceted strategy, with a multidisciplinary approach, including telehealth tools (decision support systems, short message service, telediagnosis), continued education with an approach to issues related to the care of people with hypertension and diabetes in primary care, including pharmacological and non-pharmacological treatment and behavioral change. The project has actions focused on professionals and patients., Conclusions: This study consists of a multidimensional strategy with multidisciplinary approach using digital health to improve the control of hypertension and/or DM in the primary health care setting. We expect to provide the basis for implementing an innovative management program for hypertension and DM in Brazil, aiming to reduce the present and future burden of these diseases in Brazil and other LMICs., Clinical Trial Identifier: This study was registered in ClinicalTrials.gov. (NCT05660928)., Competing Interests: Conflict of interest None reported., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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7. Intermittent high-intensity exercise for pre- to established hypertension: A systematic review and meta-analysis.
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Teixeira JMM, Motta-Santos D, Milanovic Z, Pereira RL, Krustrup P, and Póvoas S
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- Adult, Humans, Middle Aged, Blood Pressure, Exercise, Team Sports, Hypertension, High-Intensity Interval Training
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Objective: To determine the impact of intermittent high-intensity exercise training ([IHIE], including high-intensity interval training [HIIT] and recreational team sports [RTS]) on systolic (SBP) and diastolic blood pressure (DBP) in adults with pre- to established arterial hypertension., Data Sources: MEDLINE, Cochrane Library, Embase, and SPORTDiscus., Eligibility Criteria: Randomized controlled trials (RCTs) comparing the impact of IHIE on BP versus a non-exercise control., Data Collection and Analysis: Two authors independently conducted all procedures. Mean differences were calculated using random-effects model. The certainty of the evidence was assessed with GRADE., Results: Twenty-seven RCTs (18 HIIT and 9 RTS) were analyzed, with median duration of 12 weeks. Participants' (n = 946) median age was 46 years. Overall, IHIE decreased SBP (-3.29 mmHg; 95% CI: -5.19, -1.39) and DBP (-2.62 mmHg; 95% CI: -3.79, -1.44) compared to the control group. IHIE elicited higher decreases in office SBP and DBP of hypertensive subjects (SBP: -7.13 mmHg, [95% CI: -10.12, -4.15]; DBP: -5.81 mmHg, [95% CI: -7.94, -3.69]) than pre-hypertensive (SBP: -2.14 mmHg, [95% CI: -4.36, -0.08]; DBP: -1.83 mmHg, [95% CI: -2.99, -0.67]). No significant differences were found between HIIT (SBP: -2.12 mmHg, [95% CI: -4.78, -0.54]; DBP: -1.89 mmHg, [95% CI: -3.32, -0.48]) and RTS (SBP: -4.18 mmHg, [95% CI: -7.19, -2.43]; DBP: -4.04 mmHg, [95% CI: -6.00, -2.09]). These findings present low/very low certainty of evidence. No adverse cardiovascular events were reported., Conclusions: IHIE appears to be safe and to promote substantial decreases in BP, particularly in patients with hypertension. However, the certainty of evidence was low/very low., Protocol: CRD42020163575., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2023
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8. Nutritional implications in the mechanistic link between the intestinal microbiome, renin-angiotensin system, and the development of obesity and metabolic syndrome.
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Guimarães VHD, Marinho BM, Motta-Santos D, Mendes GDRL, and Santos SHS
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- Humans, Renin-Angiotensin System, Obesity metabolism, Prebiotics, Metabolic Syndrome metabolism, Gastrointestinal Microbiome physiology, Probiotics
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Obesity and metabolic disorders represent a significant global health problem and the gut microbiota plays an important role in modulating systemic homeostasis. Recent evidence shows that microbiota and its signaling pathways may affect the whole metabolism and the Renin-Angiotensin System (RAS), which in turn seems to modify microbiota. The present review aimed to investigate nutritional implications in the mechanistic link between the intestinal microbiome, renin-angiotensin system, and the development of obesity and metabolic syndrome components. A description of metabolic changes was obtained based on relevant scientific literature. The molecular and physiological mechanisms that impact the human microbiome were addressed, including the gut microbiota associated with obesity, diabetes, and hepatic steatosis. The RAS interaction signaling and modulation were analyzed. Strategies including the use of prebiotics, symbiotics, probiotics, and biotechnology may affect the gut microbiota and its impact on human health., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2023
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9. High-protein diet associated with resistance training reduces cardiac TNF-α levels and up-regulates MMP-2 activity in rats.
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Nogueira ME, Sousa Neto IV, Motta-Santos D, Cantuária APC, Lima SMF, Rezende TMB, Santana HAP, Petriz BA, Marqueti RC, and Almeida JA
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- Animals, Humans, Rats, Biomarkers, Interleukin-6, Matrix Metalloproteinase 2, Nitric Oxide, Tumor Necrosis Factor-alpha metabolism, Vascular Endothelial Growth Factor A, Diet, High-Protein, Resistance Training
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The consumption of high-protein diets (HPD) is associated with resistance training (RT) due to effects on metabolism. However, little is known about these effects on cardiac tissue. This study aimed to investigate effects of HPD and RT on cardiac biomarkers. 18 rats were divided into normo-protein (NPD), and HPD groups: NPD-Control, NPD-RT, HPD-Control, and HPD-RT. Interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-a), nitric oxide (NO), activity of metalloproteinase-2 (MMP-2), and vascular factor (VEGF) were analysed. RT was effective in regulating body weight, increasing strength, and reducing food consumption ( p < .05). HPD induces higher levels of interleukin 6 ( p = .0169), and lowers NO ( p < .0001). When associated with RT, the HPD decreases levels of tumour necrosis factor alpha, while enhances NO, and MMP activity ( p < .05). The association of RT with HDP decreases inflammatory parameters and indicates an enhancement in the molecular parameters of cardiac tissue.
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- 2022
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10. Phosphate and IL-10 concentration as predictors of long-covid in hemodialysis patients: A Brazilian study.
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Corrêa HL, Deus LA, Araújo TB, Reis AL, Amorim CEN, Gadelha AB, Santos RL, Honorato FS, Motta-Santos D, Tzanno-Martins C, Neves RVP, and Rosa TS
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- Brazil epidemiology, Female, Hand Strength, Humans, Interleukin-10, Iron, Male, Phosphates, Renal Dialysis adverse effects, Renal Dialysis methods, Post-Acute COVID-19 Syndrome, COVID-19 complications, COVID-19 epidemiology
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Background: The global burden of persistent COVID-19 in hemodialysis (HD) patients is a worrisome scenario worth of investigation for the critical care of chronic kidney disease (CKD). We performed an exploratory post-hoc study from the trial U1111-1237-8231 with two specific aims: i) to investigate the prevalence of COVID-19 infection and long COVID symptoms from our Cohort of 178 Brazilians HD patients. ii) to identify whether baseline characteristics should predict long COVID in this sample., Methods: 247 community-dwelling older (>60 years) patients (Men and women) undergoing HD (glomerular filtration rate < 15 mL/min/1.73m
2 ) with arteriovenous fistula volunteered for this study. All patients presented hypertension and diabetes. Patients were divided in two groups: without long-COVID and with long-COVID. Body composition, handgrip strength, functional performance, iron metabolism, phosphate, and inflammatory profile were assessed. Patients were screened for 11-months after COVID-19 infection. Results were considered significant at P < 0.05., Results: We found that more than 85% of the COVID-19 infected patients presented a severe condition during the infection. In our sample, the mortality rate over 11-month follow was relatively low (8.4%) when compared to worldwide (approximately 36%). Long COVID was highly prevalent in COVID-19 survivors representing more than 80% of all cases. Phosphate and IL-10 were higher in the long COVID group, but only phosphate higher than 5.35 mg/dL appears to present an increased prevalence of long COVID, dyspnea, and fatigue., Conclusion: There was a high prevalence of COVID-19 infection and long COVID in HD patients from the Brazilian trial 'U1111-1237-8231'. HD clinics should be aware with phosphate range in HD patients as a possible target for adverse post-COVID events., 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 Corrêa, Deus, Araújo, Reis, Amorim, Gadelha, Santos, Honorato, Motta-Santos, Tzanno-Martins, Neves and Rosa.)- Published
- 2022
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11. Combined training is not superior to strength and aerobic training to mitigate cardiovascular risk in adult healthy men.
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Gonçalves R, Motta-Santos D, Szmuchrowski L, Couto B, Soares YM, Damasceno VO, Pedrosa GF, Drummond MDM, Lima FV, and Silva AS
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Although the beneficial effects of aerobic training on cardiovascular risk factors are evident, the potential beneficial effect of strength and combined training on these risk factors is controversial. This study aimed to evaluate the effect of aerobic and strength training programmes, performed alone or in combination, on cardiovascular risk factors in sedentary, apparently healthy and non-obese adult men. The study was conducted with 37 subjects who were randomly divided into the following groups: aerobic (AG), combined (ASG), strength (SG) and control (CG). The exercise programmes were performed three times a week and lasted approximately 50 minutes. Dietary intake, anthropometry, blood pressure, muscular strength, aerobic capacity, lipid profile and glycaemic control were assessed before and after 12 weeks of the intervention. One-way analysis of variation (ANOVA) for baseline, and ANOVA for repeated measures were used to assess differences between the initial and final time points of the four groups. Changes in blood pressure and glycaemic control were not significant in any of the groups. No differences were observed in LDL-C between training groups. HDL-C increased significantly only in the AG. In conclusion, if minimal changes in the lipid profile are needed, an aerobic training programme can provide possible benefits for HDL-C in apparently healthy and non-obese adult men., Competing Interests: The authors declare no conflict of interest., (Copyright © Biology of Sport 2022.)
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- 2022
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12. Letter to the Editor Regarding "Influence of Baseline Physical Activity as a Modifying Factor on COVID-19 Mortality: A Single-Center, Retrospective Study".
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de Lucena Alves CP, Dos Santos MR, and Motta-Santos D
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- 2022
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13. The effect of the protective face mask on cardiorespiratory response during aerobic exercise.
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do Prado DML, Silvino VO, Motta-Santos D, and Dos Santos MAP
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- Cardiovascular Physiological Phenomena, Humans, Exercise physiology, Masks adverse effects, Physical Endurance physiology, Respiratory Physiological Phenomena
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The protective face mask (PFM) has been widely used for safety purposes and, after the advent of the COVID-19 pandemic, its use is growing steadily, not only among healthcare personnel but also the general population. While the PFM is important to preserve the wearer from contaminating agents present in the airflow, they are well known to increase the subjective perception of breathing difficulty. Although some studies have demonstrated that PFM use worsens exercise tolerance, several studies state that there is no such limitation with the use of PFM. Moreover, no serious adverse effects during physical exercise have been found in the literature. Physical exercise represents a significant challenge to the human body through a series of integrated changes in function that involve most of its physiologic systems. In this respect, cardiovascular and respiratory systems provide the capacity to sustain physical tasks over extended periods. Within this scenario, both convective oxygen (O
2 ) transport (product of arterial O2 content × blood flow) to the working locomotor muscles and O2 diffusive transport from muscle capillaries to mitochondria are of paramount importance to endurance performance. Interestingly, the effects of PFM on cardiorespiratory response during aerobic exercise depends on the type of mask and exercise (i.e., walking, running, or cycling), the ventilatory demands, arterial oxygen levels, maximal oxygen consumption and endurance performance. The purpose of this review is to elucidate the effect of protective face mask-wearing on (1) cardiorespiratory responses during aerobic exercise and (2) endurance performance., (© 2022 John Wiley & Sons Australia, Ltd.)- Published
- 2022
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14. Angiotensin-(1-7)/Mas receptor modulates anti-inflammatory effects of exercise training in a model of chronic allergic lung inflammation.
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Gregório JF, Magalhães GS, Rodrigues-Machado MG, Gonzaga KER, Motta-Santos D, Cassini-Vieira P, Barcelos LS, Vieira MAR, Santos RAS, and Campagnole-Santos MJ
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- Angiotensin I blood, Animals, Asthma blood, Asthma metabolism, Disease Models, Animal, Exercise Therapy, Male, Mice, Inbred BALB C, Peptide Fragments blood, Pneumonia blood, Pneumonia metabolism, Mice, Angiotensin I metabolism, Asthma therapy, Peptide Fragments metabolism, Pneumonia therapy
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Aims: Exercise training increases circulating and tissue levels of angiotensin-(1-7) [Ang-(1-7)], which was shown to attenuate inflammation and fibrosis in different diseases. Here, we evaluated whether Ang-(1-7)/Mas receptor is involved in the beneficial effects of aerobic training in a chronic model of asthma., Material and Methods: BALB/c mice were subjected to a protocol of asthma induced by ovalbumin sensitization (OVA; 4 i.p. injections) and OVA challenge (3 times/week for 4 weeks). Simultaneously to the challenge period, part of the animals was continuously treated with Mas receptor antagonist (A779, 1 μg/h; for 28 days) and trained in a treadmill (TRE; 60% of the maximal capacity, 1 h/day, 5 days/week during 4 weeks). PGC1-α mRNA expression (qRT-PCR), plasma IgE and lung cytokines (ELISA), inflammatory cells infiltration (enzymatic activity assay) and airway remodeling (by histology) were evaluated., Key Findings: Blocking the Mas receptor with A779 increased IgE and IL-13 levels and prevented the reduction in extracellular matrix deposition in airways in OVA-TRE mice. Mas receptor blockade prevented the reduction of myeloperoxidase activity, as well as, prevented exercise-induced IL-10 increase. These data show that activation of Ang-(1-7)/Mas receptor pathway is involved in the anti-inflammatory and anti-fibrotic effects of aerobic training in an experimental model of chronic asthma., Significance: Our results support exercise training as a non-pharmacological tool to defeat lung remodeling induced by chronic pulmonary inflammation. Further, our result also supports development of new therapy based on Ang-(1-7) or Mas agonists as important tool for asthma treatment in those patients that cannot perform aerobic training., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2021
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15. Alamandine but not angiotensin-(1-7) produces cardiovascular effects at the rostral insular cortex.
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Marins FR, Oliveira AC, Qadri F, Motta-Santos D, Alenina N, Bader M, Fontes MAP, and Santos RAS
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- Animals, Cerebral Cortex physiology, Ligands, Male, Microinjections, Nerve Tissue Proteins metabolism, Proto-Oncogene Mas, Proto-Oncogene Proteins agonists, Proto-Oncogene Proteins metabolism, Rats, Sprague-Dawley, Receptors, G-Protein-Coupled metabolism, Sympathetic Nervous System physiology, Rats, Angiotensin I pharmacology, Arterial Pressure drug effects, Cardiovascular System innervation, Cerebral Cortex drug effects, Heart Rate drug effects, Kidney innervation, Nerve Tissue Proteins agonists, Oligopeptides pharmacology, Peptide Fragments pharmacology, Receptors, G-Protein-Coupled agonists, Sympathetic Nervous System drug effects
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Experiments aimed to evaluate the tissue distribution of Mas-related G protein-coupled receptor D (MrgD) revealed the presence of immunoreactivity for the MrgD protein in the rostral insular cortex (rIC), an important area for autonomic and cardiovascular control. To investigate the relevance of this finding, we evaluated the cardiovascular effects produced by the endogenous ligand of MrgD, alamandine, in this brain region. Mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded in urethane anesthetized rats. Unilateral microinjection of equimolar doses of alamandine (40 pmol/100 nL), angiotensin-(1-7), angiotensin II, angiotensin A, and Mas/MrgD antagonist d-Pro
7 -Ang-1-7 (50 pmol/100 nL), Mas antagonist A779 (100 pmol/100 nL), or vehicle (0.9% NaCl) were made in different rats ( n = 4-6/group) into rIC. To verify the specificity of the region, a microinjection of alamandine was also performed into intermediate insular cortex (iIC). Microinjection of alamandine in rIC produced an increase in MAP (Δ = 15 ± 2 mmHg), HR (Δ = 36 ± 4 beats/min), and RSNA (Δ = 31 ± 4%), but was without effects at iIC. Strikingly, an equimolar dose of angiotensin-(1-7) at rIC did not produce any change in MAP, HR, and RSNA. Angiotensin II and angiotensin A produced only minor effects. Alamandine effects were not altered by A-779, a Mas antagonist, but were completely blocked by the Mas/MrgD antagonist d-Pro7 -Ang-(1-7). Therefore, we have identified a brain region in which alamandine/MrgD receptor but not angiotensin-(1-7)/Mas could be involved in the modulation of cardiovascular-related neuronal activity. This observation also suggests that alamandine might possess unique effects unrelated to angiotensin-(1-7) in the brain.- Published
- 2021
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16. Association of physical activity levels and the prevalence of COVID-19-associated hospitalization.
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de Souza FR, Motta-Santos D, Dos Santos Soares D, de Lima JB, Cardozo GG, Guimarães LSP, Negrão CE, and Dos Santos MR
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- Adolescent, Adult, Aged, Aged, 80 and over, Brazil epidemiology, COVID-19 diagnosis, COVID-19 etiology, COVID-19 therapy, Child, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Prevalence, Protective Factors, Quarantine, Respiration, Artificial statistics & numerical data, Risk Factors, Severity of Illness Index, Survivors, Young Adult, COVID-19 epidemiology, Exercise, Health Behavior, Hospitalization statistics & numerical data
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Objectives: We compared physical activity levels before the outbreak and quarantine measures with COVID-19-associated hospitalization prevalence in surviving patients infected with SARS-CoV-2. Additionally, we investigated the association of physical activity levels with symptoms of the disease, length of hospital stay, and mechanical ventilation., Design: Observational, cross-sectional., Methods: Between June 2020 and August 2020, we invited Brazilian survivors and fully recovered patients infected with SARS-CoV-2 to respond to an online questionnaire. We shared the electronic link to the questionnaire on the internet. We collected data about clinical outcomes (symptoms, medications, hospitalization, and length of hospital stay) and cofactors, such as age, sex, ethnicity, preexisting diseases, socioeconomic and educational, and physical activity levels using the International Physical Activity Questionnaire (IPAQ short version)., Results: Out of 938 patients, 91 (9.7%) were hospitalized due to COVID-19. In a univariate analysis, sex, age, and BMI were all associated with hospitalizations due to COVID-19. Men had a higher prevalence of hospitalization (66.6%, p = 0.013). Patients older than 65 years, obese, and with preexisting disease had a higher prevalence of COVID-19-related hospitalizations. In a multivariate regression model, performance of at least 150 min/wk (moderate) and/or 75 min/wk (vigorous) physical activity was associated with a lower prevalence of hospitalizations after adjustment for age, sex, BMI, and preexisting diseases (PR = 0.657; p = 0.046)., Conclusions: Sufficient physical activity levels were associated with a lower prevalence of COVID-19-related hospitalizations. Performing at least 150 min a week of moderate-intensity, or 75 min a week of vigorous-intensity physical activity was associated with 34.3% reduction in prevalence., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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17. Increased circulating levels of angiotensin-(1-7) in severely ill COVID-19 patients.
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Valle Martins AL, da Silva FA, Bolais-Ramos L, de Oliveira GC, Ribeiro RC, Pereira DAA, Annoni F, Diniz MML, Silva TGF, Zivianni B, Cardoso AC, Martins JC, Motta-Santos D, Campagnole-Santos MJ, Taccone FS, Verano-Braga T, and Santos RAS
- Abstract
This letter reports an unexpected increase of the ACE2 product angiotensin-(1-7) and a parallel decrease of its substrate angiotensin II, suggesting a dysregulation of the renin-angiotensin system towards angiotensin-(1-7) formation in #COVID19 patients https://bit.ly/3xFXuTU., Competing Interests: Conflict of interest: A.L. Valle Martins reports a patent pending (BR1020210009950). Conflict of interest: F.A. da Silva has nothing to disclose. Conflict of interest: L. Bolais-Ramos has nothing to disclose. Conflict of interest: G.C. de Oliveira has nothing to disclose. Conflict of interest: R.C. Ribeiro has nothing to disclose. Conflict of interest: D.A.A. Pereira has nothing to disclose. Conflict of interest: F. Annoni has nothing to disclose. Conflict of interest: M.M.L. Diniz has nothing to disclose. Conflict of interest: T.G.F. Silva has nothing to disclose. Conflict of interest: B. Ziviani has nothing to disclose. Conflict of interest: A.C. Cardoso has nothing to disclose. Conflict of interest: J.C. Martins has nothing to disclose. Conflict of interest: D. Motta-Santos has nothing to disclose. Conflict of interest: M.J. Campagnole-Santos has nothing to disclose. Conflict of interest: F.S. Taccone has nothing to disclose. Conflict of interest: T. Verano-Braga has nothing to disclose. Conflict of interest: R.A.S. Santos reports patents planned., (Copyright ©The authors 2021.)
- Published
- 2021
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18. Angiotensin-(1-7) oral formulation improves physical performance in mountain bike athletes: a double-blinded crossover study.
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de Moura SS, Mendes ATP, de Assis Dias Martins-Júnior F, Totou NL, Coelho DB, Oliveira EC, Motta-Santos D, Dos Santos RAS, and Becker LK
- Abstract
Background: The ECA2/Ang-(1-7)/Mas axis is shown to be involved in effects mediated by physical exercise, as it can induce the release of nitric oxide (ON) and bradykinin (BK), which are potent vasodilators. The vasodilating action the NO/BK can contribute to increased metabolic efficiency in muscle tissue and central nervous system. The formulation HPβ-CD-Ang-(1-7) through its mechanisms of action can be a promising supplement to aid in the maintenance and improvement of performance and may also favor recovery during competitions. The premise of this study was to investigate the effects of acute oral supplementation HPβ-CD-Ang-(1-7) on the performance of mountain bike (MTB) practitioners., Methods: Fourteen recreational athletes, involved in training programs for at least one year, participated in this crossover design study. Subjects underwent two days of testing with a seven-day interval. HPβ-CD-Ang-(1-7) (1.75 mg) and HPβCD-Placebo were provided in capsules three hours prior to tests. To determine the safety of the HPβ-CD-Ang-(1-7) formulation associated with physical effort, cardiovascular parameters heart rate (HR) and blood pressure (BP) were analyzed. Physical performance was measured using maximal oxygen uptake (VO
2 ), total exercise time (TET), mechanical work (MW), mechanical efficiency (ME), and rating of perceived exertion (RPE). Respiratory exchange coefficient (REC), lactate and non-esterified fatty acids (NEFAs) were measured. Maximal incremental tests were performed on a progressively loaded leg cycle ergometer., Results: There were no significant differences in terms of HR or BP at rest and maximum effort between the HPβ-CD-Ang-(1-7) and placebo groups. The VO2 max showed significant differences (p = 0.04). It was higher in the Ang-(1-7)condition (66.15 mlO2 .kg- 1 .min- 1 ) compared to the placebo (60.72 mlO2 .kg- 1 .min- 1 ). This was also observed for TET (Ang-(1-7) 39.10 min vs. placebo 38.14 min; p = 0.04), MW (Ang-(1-7) 156.7 vs. placebo 148.2; p = 0.04), and at the lowest RPE (Ang-(1-7) vs. placebo; p = 0.009). No significant differences were observed for REC, NEFAs, or Lactate., Conclusions: These results suggest that HPβ-CD-Ang-(1-7) improves the physical performance of MTB recreational athletes and could be a promising supplement., Trial Registration: RBR-2 × 56pw8, registered January 15th, 2021. The study was prospectively registered.- Published
- 2021
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19. Master athletes have longer telomeres than age-matched non-athletes. A systematic review, meta-analysis and discussion of possible mechanisms.
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Aguiar SS, Sousa CV, Santos PA, Barbosa LP, Maciel LA, Coelho-Júnior HJ, Motta-Santos D, Rosa TS, Degens H, and Simões HG
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- Aged, Athletes, Humans, Oxidative Stress, Aging, Telomere
- Abstract
The aim of this systematic review and meta-analysis was 1) to assess whether master athletes have longer telomeres than age-matched non-athletes and 2) discuss possible underlying mechanisms underlying telomere length preservation in master athletes. A literature search was performed in PubMed, Web of Science, Scopus and SPORTDiscus up to August 2020. Only original articles published in peer-reviewed journals that compared telomere length between master athletes and aged-matched non-athletes were included. Eleven studies fulfilled eligibility criteria and were included in the final analysis. Overall, 240 master athletes (51.9±7.5 years) and 209 age-matched non-athletes (50.1±9.1 years) were analyzed. Master athletes had been participating in high-level competitions for approximately 16.6 years. Pooled analyses revealed that master athletes had longer telomeres than aged-matched non-athletes (SMD=0.89; 95% CI=0.45 to 1.33; p<0.001). Master athletes showed lower pro-oxidant damage (SMD=0.59; 95% CI=0.26 to 0.91; p<0.001) and higher antioxidant capacity (SMD=-0.46; 95% CI=-0.89 to -0.03; p=0.04) than age-matched non-athletes. Further, greater telomere length in master athletes is associated with lower oxidative stress and chronic inflammation, and enhanced shelterin protein expression and telomerase activity. In conclusion, 1) master athletes have longer telomeres than age-matched non-athletes, which may be the result of 2) lower levels of oxidative stress and chronic inflammation, and elevated shelterin expression and telomerase activity., (Copyright © 2020. Published by Elsevier Inc.)
- Published
- 2021
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20. ACE2 in the renin-angiotensin system.
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Verano-Braga T, Martins ALV, Motta-Santos D, Campagnole-Santos MJ, and Santos RAS
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- COVID-19 virology, Humans, Oligopeptides pharmacology, Renin-Angiotensin System physiology, SARS-CoV-2 pathogenicity, Angiotensin-Converting Enzyme 2 drug effects, Angiotensin-Converting Enzyme Inhibitors pharmacology, Renin-Angiotensin System drug effects, SARS-CoV-2 drug effects, COVID-19 Drug Treatment
- Abstract
In 2020 we are celebrating the 20th anniversary of the angiotensin-converting enzyme 2 (ACE2) discovery. This event was a landmark that shaped the way that we see the renin-angiotensin system (RAS) today. ACE2 is an important molecular hub that connects the RAS classical arm, formed mainly by the octapeptide angiotensin II (Ang II) and its receptor AT1, with the RAS alternative or protective arm, formed mainly by the heptapeptides Ang-(1-7) and alamandine, and their receptors, Mas and MrgD, respectively. In this work we reviewed classical and modern literature to describe how ACE2 is a critical component of the protective arm, particularly in the context of the cardiac function, coagulation homeostasis and immune system. We also review recent literature to present a critical view of the role of ACE2 and RAS in the SARS-CoV-2 pandemic., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Published
- 2020
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21. Maternal obesity modulates both the renin-angiotensin system in mice dams and fetal adiposity.
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Cerri GC, Motta-Santos D, Andrade JMO, Rezende LF, Santos RASD, and Santos SHS
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- Animals, Animals, Newborn, Body Composition, Body Weight, Female, Fetus metabolism, Glucose Tolerance Test, Insulin Resistance, Maternal Nutritional Physiological Phenomena, Mice, Mice, Inbred C57BL, Pregnancy, Proto-Oncogene Mas, Adiposity, Obesity, Maternal metabolism, Renin-Angiotensin System
- Abstract
Obesity is a chronic multifactorial disease and is currently a public health problem. Maternal obesity during pregnancy is more dangerous as it impairs the health of the mother and future generations. Obesity leads to several metabolic disorders. Since white adipose tissue is an endocrine tissue, obesity often leads to disordered secretion of inflammatory, glycemic, lipid and renin-angiotensin system (RAS) components. The RAS represents a link between obesity and its metabolic consequences. Therefore, our goal was to evaluate the possible changes caused by a high-fat diet in RAS-related receptor expression in the uterus and placenta of pregnant mice and determine the underlying effects of these changes in the fetuses' body composition. Breeding groups were formed after obesity induction by high-fat (HF) diet. Dams and fetuses were euthanized on the 19th day of the gestational period. The HF diet effectively induced obesity, glucose intolerance and insulin resistance in mice. Fetuses born from HF dams showed increased body weight and adiposity. Both results were accompanied by increased AT
1 R expression in placenta and uterus together with increased angiotensin-converting enzyme expression in the uterus and a decreased expression of MAS1 in placenta of HF dams. These results suggest a link between RAS, maternal obesity induced by HF diet and the fetuses' body adiposity. This new path now can be more thoroughly explored., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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22. Angiotensin-(1-7) and Obesity: Role in Cardiorespiratory Fitness and COVID-19 Implications.
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Motta-Santos D, Santos RAS, and Santos SHS
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- Angiotensin I, Betacoronavirus, COVID-19, Humans, Obesity, Peptide Fragments, SARS-CoV-2, Cardiorespiratory Fitness, Coronavirus Infections, Infections, Pandemics, Pneumonia, Viral
- Published
- 2020
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23. Activation of Ang-(1-7)/Mas Receptor Is a Possible Strategy to Treat Coronavirus (SARS-CoV-2) Infection.
- Author
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Magalhaes GS, Rodrigues-Machado MDG, Motta-Santos D, Campagnole-Santos MJ, and Santos RAS
- Published
- 2020
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24. Does Longer Leukocyte Telomere Length and Higher Physical Fitness Protect Master Athletes From Consequences of Coronavirus (SARS-CoV-2) Infection?
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Simões HG, Rosa TS, Sousa CV, Aguiar SDS, Motta-Santos D, Degens H, Korhonen MT, and Campbell CSG
- Published
- 2020
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25. High-Protein Diet Associated with Bocaiuva Supplementation Decreases Body Fat and Improves Glucose Tolerance in Resistance-Trained Rats.
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Almeida JA, Santana HAP, Motta-Santos D, Nogueira ME, Silva KKS, Miotto H, Medeiros CS, Faria-Ravagnani CC, Voltarelli FA, and Guimarães RCA
- Subjects
- Adipose Tissue metabolism, Adiposity, Animals, Diet, High-Protein, Dietary Proteins analysis, Glucose Tolerance Test, Intra-Abdominal Fat metabolism, Physical Conditioning, Animal, Rats, Rats, Wistar, Resistance Training, Arecaceae chemistry, Blood Glucose metabolism, Dietary Proteins metabolism, Dietary Supplements analysis, Plant Extracts administration & dosage
- Abstract
High-protein diets (HPDs) are widely used for health and performance. However, the combination of whey protein and natural foods ( i.e. , fruits) is still unclear. Thus, we evaluated the role of supplemental HPD with Bocaiuva ( Acrocomia sp.) in metabolic and body composition parameters of rats submitted to resistance training (RT). Wistar rats (203.3 ± 30 g) were randomly allocated to five groups: normoproteic control (CON, n = 5), sedentary high-protein (SH, n = 5), RT + H (trained high-protein [TH], n = 5), sedentary+Bocaiuva (SH+B, n = 4), and RT+Bocaiuva (TH+B, n = 4) diet groups. After 12 weeks of RT, the maximal strength increased in both trained groups ( P < .05). The TH + B group had lower values of adiposity index (AI) (3.8 ± 0.7% vs. 6.8 ± 1.3%) and visceral fat (0.038 ± 0.004 g/g vs. 0.067 ± 0.012 g/g) compared with the SH group, respectively ( P < .05). The other groups did not show differences in values of AI (CON, 5.4 ± 1.6%, TH, 5.4 ± 1.3%, and SH+B, 5.5 ± 1.2%). In addition, the fasting glucose of trained groups (TH, 106.0 ± 4.5, and TH+B, 100.4 ± 13.5 dL/mg) was significantly lower when compared with controls (SH, 120.0 ± 14.4, and SH+B, 119 ± 6.4 dL/mg) ( P < .05). Bocaiuva combined with an HPD reduced visceral fat and AI in addition to improving glucose tolerance of rats submitted to RT.
- Published
- 2020
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26. Oral formulation angiotensin-(1-7) therapy attenuates pulmonary and systemic damage in mice with emphysema induced by elastase.
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Bastos AC, Magalhães GS, Gregório JF, Matos NA, Motta-Santos D, Bezerra FS, Santos RAS, Campagnole Santos MJ, and Rodrigues-Machado MG
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- Administration, Oral, Animals, Disease Models, Animal, Homeostasis drug effects, Interleukin-1beta metabolism, Locomotion drug effects, Lung metabolism, Male, Mice, Mice, Inbred C57BL, Pulmonary Alveoli drug effects, Pulmonary Alveoli metabolism, Pulmonary Emphysema metabolism, Swine, Angiotensin I pharmacology, Lung drug effects, Pancreatic Elastase pharmacology, Peptide Fragments pharmacology, Pulmonary Emphysema drug therapy
- Abstract
Angiotensin-(1-7) [Ang-(1-7)], a peptide of the renin-angiotensin system, has anti-inflammatory, anti-fibrotic and antiproliferative effects in acute or chronic inflammatory disease of respiratory system. In this study, we evaluated the effect of treatment with Ang-(1-7) on pulmonary tissue damage and behavior of mice submitted to experimental model of elastase-induced pulmonary emphysema (PE). Initially, male C57BL/6 mice were randomly assigned into two main groups: control (CTRL) and PE. In the PE group, the animals received three intratracheal instillations of pancreatic porcine elastase (PPE) at 1-week intervals (0.2 IU in 50 μL of saline). The CTRL group received the same volume of saline solution (50 μL). Twenty-four hours after the last instillation, animals of the PE group were randomly divided into two groups: PE and PE + Ang-(1-7). The PE + Ang-(1-7) group was treated with 60 μg/kg of Ang-(1-7) and 92 μg kg of HPβCD in gavage distilled water, 100 μl. The CTRL and PE groups were treated with vehicle (HPβCD- 92 μg/kg in distilled water per gavage, 100 μl), orally daily for 3 weeks. On the 19th day of treatment, all groups were tested in relation to locomotor activity and exploratory behavior. After 48 h, the animals were euthanized and lungs were collected. The animals of PE group presented rupture of alveolar walls and consequently reduction of alveolar tissue area. Treatment with Ang-(1-7) partially restored the alveolar tissue area. The PE reduced the locomotor activity and the exploratory behavior of the mice in relation to the control group. Treatment with Ang-(1-7) attenuated this change. In addition, it was observed that Ang-(1-7) reduced lung levels of IL-1β and increased levels of IL-10. These results show an anti-inflammatory effect of Ang-(1-7), inducing the return of pulmonary homeostasis and attenuation of the behavioral changes in experimental model of PE by elastase., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2019 Elsevier GmbH. All rights reserved.)
- Published
- 2020
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27. High-intensity aerobic training lowers blood pressure and modulates the renal renin-angiotensin system in spontaneously hypertensive rats.
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Almeida JA, Motta-Santos D, Petriz BA, Gomes CPDC, Nogueira ME, Pereira RW, Araújo RC, Prestes J, and Franco OL
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- Animals, Disease Models, Animal, Kidney metabolism, Male, Rats, Rats, Inbred SHR, Treatment Outcome, Blood Pressure physiology, Hypertension physiopathology, Hypertension therapy, Physical Conditioning, Animal methods, Physical Conditioning, Animal physiology, Renin-Angiotensin System physiology
- Abstract
Background: This study aimed to verify the effects of high-intensity aerobic training (HIAT) on BP control and renin-angiotensin system (RAS) components in renal tissue of SHR. Ten SHRs received HIAT or control for 8-weeks. At the end of the training, the SBP showed a reduction of ~ 30mmHg (p < .01) in HIAT and increased by ~ 15 mmHg in the control group. HIAT resulted in a higher release of nitrite, IL-6, ACE2 and ATR2. These results indicated an association between BP, NO and renal RAS. Abbreviations : JAA: writing, carried out all experimental procedures, performed statistical analysis, original draft and revised manuscript DMS: data interpretation, formal analysis, writing, editing and revised manuscript BAP: carried all experimental procedures, revised manuscritpt CPCG: carried all experimental procedures, revised manuscritpt MEN: experimental procedures, revised manuscript and data interpretation RWP: drafted and revised manuscript RCA: writing, experimental procedures, revised manuscript JP: writing, data interpretation and revised manuscript OLF: writing, original draft and revised manuscript.
- Published
- 2020
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28. Lifetime overproduction of circulating angiotensin-(1-7) in rats attenuates the increase in skeletal muscle damage biomarkers after exhaustive exercise.
- Author
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Becker LK, Totou NL, Oliveira MF, Coelho DB, de Oliveira EC, Motta-Santos D, Silami-Garcia E, Campagnole-Santos MJ, and Santos RAS
- Subjects
- Angiotensin I, Animals, Biomarkers, Peptide Fragments, Rats, Rats, Sprague-Dawley, Muscle, Skeletal
- Abstract
Angiotensin-(1-7) (Ang-[1-7]) can modulate glucose metabolism and protect against muscular damage. The aim of this study was to investigate the influence of lifetime increase of circulating levels of Ang-(1-7) at exhaustive swimming exercise (ESE). Sprague-Dawley (SD) and transgenic rats TGR(A1-7)3292 (TR) which overproduce Ang-(1-7) (2.5-fold increase) were submitted to ESE. The data showed no differences in time to exhaustion (SD: 4.90 ± 1.37 h vs. TR: 5.15 ± 1.15 h), creatine kinase, and transforming growth factor beta (TGF-β). Lactate dehydrogenase (SD: 219.9 ± 12.04 U/L vs. TR: 143.9 ± 35.21 U/L) and α-actinin (SD: 336.7 ± 104.5 U/L vs. TR: 224.6 ± 82.45 U/L) values were significantly lower in TR. There was a significant decrease in the range of blood glucose levels (SD: -41.4 ± 28.32 mg/dl vs. TR: -13.08 ± 39.63 mg/dl) in SD rats. Muscle (SD: 0.06 ± 0.02 mg/g vs. TR: 0.13 ± 0.01 mg/g) and hepatic glycogen (SD: 0.66 ± 0.36 mg/g vs. TG: 2.24 ± 1.85 mg/g) in TR were higher. The TR presented attenuation of the increase in skeletal muscle damage biomarkers and of the changes in glucose metabolism after ESE., Competing Interests: None
- Published
- 2019
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29. Alamandine attenuates arterial remodelling induced by transverse aortic constriction in mice.
- Author
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de Souza-Neto FP, Silva MME, Santuchi MC, de Alcântara-Leonídio TC, Motta-Santos D, Oliveira AC, Melo MB, Canta GN, de Souza LE, Irigoyen MCC, Campagnole-Santos MJ, Guatimosim S, Santos RAS, and da Silva RF
- Subjects
- Animals, Aorta, Thoracic metabolism, Aorta, Thoracic pathology, Aorta, Thoracic physiopathology, Aortic Diseases metabolism, Aortic Diseases pathology, Aortic Diseases physiopathology, Cytokines genetics, Cytokines metabolism, Disease Models, Animal, Fibrosis, Inflammation Mediators metabolism, Male, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 metabolism, Mice, Inbred C57BL, Receptor, Angiotensin, Type 1 genetics, Receptor, Angiotensin, Type 1 metabolism, Receptors, G-Protein-Coupled agonists, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Renin-Angiotensin System drug effects, Signal Transduction drug effects, Anti-Inflammatory Agents pharmacology, Aorta, Thoracic drug effects, Aortic Diseases prevention & control, Oligopeptides pharmacology, Vascular Remodeling drug effects
- Abstract
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.)- Published
- 2019
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30. Genetic deletion of the alamandine receptor MRGD leads to dilated cardiomyopathy in mice.
- Author
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Oliveira AC, Melo MB, Motta-Santos D, Peluso AA, Souza-Neto F, da Silva RF, Almeida JFQ, Canta G, Reis AM, Goncalves G, Cerri G, Coutinho D, Guedes de Jesus IC, Guatimosim S, Linhares ND, Alenina N, Bader M, Campagnole-Santos MJ, and Santos RAS
- Subjects
- Animals, Cardiomyopathy, Dilated metabolism, Cardiomyopathy, Dilated pathology, Cells, Cultured, Female, Male, Mice, Mice, Inbred C57BL, Myocardial Contraction, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Receptors, G-Protein-Coupled metabolism, Ventricular Remodeling, Cardiomyopathy, Dilated genetics, Gene Deletion, Receptors, G-Protein-Coupled genetics
- Abstract
We have recently described a new peptide of the renin-angiotensin system, alamandine, a derivative of angiotensin-(1-7). Mas-related G protein-coupled receptor member D (MrgD) was identified as its receptor. Although similar cardioprotective effects of alamandine to those of angiotensin-(1-7) have been described, the significance of this peptide in heart function is still elusive. We aimed to evaluate the functional role of the alamandine receptor MrgD in the heart using MrgD-deficient mice. MrgD was localized in cardiomyocytes by immunofluorescence using confocal microscopy. High-resolution echocardiography was performed in wild-type and MrgD-deficient mice (2 and 12 wk old) under isoflurane anesthesia. Standard B-mode images were obtained in the right and left parasternal long and short axes for morphological and functional assessment and evaluation of cardiac deformation. Additional heart function evaluation was performed using Langendorff isolated heart preparations and inotropic measurements of isolated cardiomyocytes. Immunofluorescence indicated that the MrgD receptor is expressed in cardiomyocytes, mainly in the membrane and perinuclear and nuclear regions. Echocardiography showed left ventricular remodeling and severe dysfunction in MrgD-deficient mice. Strikingly, MrgD-deficient mice presented a pronounced dilated cardiomyopathy with a marked decrease in systolic function. Echocardiographic changes were supported by the data obtained in isolated hearts and inotropic measurements in cardiomyocytes. Our data add new evidence for a major role for alamandine/MrgD in the heart. Furthermore, our results indicate that we have identified a new gene implicated in dilated cardiomyopathy, unveiling a new target for translational approaches aimed to treat heart diseases. NEW & NOTEWORTHY The renin-angiotensin system is a key target for cardiovascular therapy. We have recently identified a new vasodepressor/cardioprotective angiotensin, alamandine. Here, we unmasked a key role for its receptor, Mas-related G protein-coupled receptor member D (MrgD), in heart function. The severe dilated cardiomyopathy observed in MrgD-deficient mice warrants clinical and preclinical studies to unveil its potential use in cardiovascular therapy.
- Published
- 2019
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31. Fast and slow-twitching muscles are differentially affected by reduced cholinergic transmission in mice deficient for VAChT: A mouse model for congenital myasthenia.
- Author
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Magalhães-Gomes MPS, Motta-Santos D, Schetino LPL, Andrade JN, Bastos CP, Guimarães DAS, Vaughan SK, Martinelli PM, Guatimosim S, Pereira GS, Coimbra CC, Prado VF, Prado MAM, Valdez G, and Guatimosim C
- Subjects
- Acetylcholine antagonists & inhibitors, Animals, Disease Models, Animal, Mice, Transgenic, Muscle, Skeletal drug effects, Myasthenic Syndromes, Congenital genetics, Neuromuscular Junction metabolism, Vesicular Acetylcholine Transport Proteins metabolism, Acetylcholine metabolism, Muscle, Skeletal metabolism, Myasthenic Syndromes, Congenital metabolism, Synaptic Vesicles metabolism
- Abstract
Congenital myasthenic syndromes (CMS) result from reduced cholinergic transmission at neuromuscular junctions (NMJs). While the etiology of CMS varies, the disease is characterized by muscle weakness. To date, it remains unknown if CMS causes long-term and irreversible changes to skeletal muscles. In this study, we examined skeletal muscles in a mouse line with reduced expression of Vesicular Acetylcholine Transporter (VAChT, mouse line herein called VAChT-KD
HOM ). We examined this mouse line for several reasons. First, VAChT plays a central function in loading acetylcholine (ACh) into synaptic vesicles and releasing it at NMJs, in addition to other cholinergic nerve endings. Second, loss of function mutations in VAChT causes myasthenia in humans. Importantly, VAChT-KDHOM present with reduced ACh and muscle weakness, resembling CMS. We evaluated the morphology, fiber type (myosin heavy chain isoforms), and expression of muscle-related genes in the extensor digitorum longus (EDL) and soleus muscles. This analysis revealed that while muscle fibers atrophy in the EDL, they hypertrophy in the soleus muscle of VAChT-KDHOM mice. Along with these cellular changes, skeletal muscles exhibit altered levels of markers for myogenesis (Pax-7, Myogenin, and MyoD), oxidative metabolism (PGC1-α and MTND1), and protein degradation (Atrogin1 and MuRF1) in VAChT-KDHOM mice. Importantly, we demonstrate that deleterious changes in skeletal muscles and motor deficits can be partially reversed following the administration of the cholinesterase inhibitor, pyridostigmine in VAChT-KDHOM mice. These findings reveal that fast and slow type muscles differentially respond to cholinergic deficits. Additionally, this study shows that the adverse effects of cholinergic transmission, as in the case of CMS, on fast and slow type skeletal muscles are reversible., (Copyright © 2018. Published by Elsevier Ltd.)- Published
- 2018
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32. Vertical Jump Is Strongly Associated to Running-Based Anaerobic Sprint Test in Teenage Futsal Male Athletes.
- Author
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Sales MM, Maciel AP, Aguiar SDS, Asano RY, Motta-Santos D, Moraes JFVN, Alves PM, Santos PA, Barbosa LP, Ernesto C, and Sousa CV
- Abstract
As one of the most popular sport modalities in Brazil, and with an exponential growth in Europe, futsal is characterized by intermittent stimulus of anaerobic high intensity sprints. The running-based anaerobic sprint test (RAST) is one of the most common tests to assess anaerobic power in futsal athletes, however, it presents both time and physical challenges. Therefore, we aimed to correlate RAST with a simpler test, the vertical jump (VJ), in teenage male futsal athletes; Methods: Thirteen volunteers were enrolled and underwent two visits to the laboratory, one for the VJ and the other for the RAST in a randomized order; Results: The association test indicates a strong and significant correlation between VJ and RAST. We conclude that VJ can be used as an alternative to RAST in teenage male futsal athletes.
- Published
- 2018
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33. Eccentric Overload Muscle Damage is Attenuated By a Novel Angiotensin- (1-7) Treatment.
- Author
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Becker LK, Totou N, Moura S, Kangussu L, Millán RDS, Campagnole-Santos MJ, Coelho D, Motta-Santos D, and Santos RAS
- Subjects
- 2-Hydroxypropyl-beta-cyclodextrin, Adult, Biomarkers blood, Creatine Kinase blood, Cytokines blood, Double-Blind Method, Excipients, Exercise Test, Female, Humans, Leukocytes, Mononuclear metabolism, Male, Muscle Strength physiology, RNA, Messenger metabolism, Young Adult, Angiotensin I therapeutic use, Dietary Supplements, Exercise physiology, Muscle, Skeletal injuries, Myalgia prevention & control, Peptide Fragments therapeutic use
- Abstract
The development of new strategies to attenuate exercise-induced muscle damage may be helpful for training regimens. The aim of this study was to determine whether a oral formulation of angiotensin Ang-(1-7)[HPβCD/Ang-(1-7)] is effective to reduce pain, and muscle damage markers after eccentric-overload exercise. HPβCD (Placebo) and HPβCD/Ang-(1-7) (Ang-(1-7) group were treated for 7 days (one capsule/day). The pain was measured by visual analogue scale, maximal strength (MS) using force platform. Blood samples were collected for cytokines and creatine kinase (CK) analysis. The Ang-(1-7)-treated group reported less pain immediately (3.46±0.64 vs. placebo 3.80±0.77 cm) and 24 h after exercise (3.07±0.71 vs. 3.73±0.58 cm placebo) and higher MS at 24 h (24±12 N) and 48 h (30±15 N) vs. placebo (-8±9 N and -10±9 N). The CK for Ang-(1-7) (0.5±0.1 and 0.9±0.2 U/L) were lower at 48 and 72 h vs. placebo (fold changes of 1.7±0.5 and 1.5±0.3 U/L). The TNF-α level was lower in the treated group post-exercise (38±2.5 pg/ml) vs. placebo (45±2.9 pg/ml) but no significant changes were observed for IL-6 and IL-10. Our data indicate that treatment with Ang-(1-7) may attenuate pain, some of the muscle damage markers and improves performance following eccentric exercise., Competing Interests: The authors declare no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)
- Published
- 2018
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34. Angiotensin-(1-7) Promotes Resolution of Eosinophilic Inflammation in an Experimental Model of Asthma.
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Magalhaes GS, Barroso LC, Reis AC, Rodrigues-Machado MG, Gregório JF, Motta-Santos D, Oliveira AC, Perez DA, Barcelos LS, Teixeira MM, Santos RAS, Pinho V, and Campagnole-Santos MJ
- Subjects
- Angiotensin I pharmacology, Animals, Apoptosis drug effects, Biomarkers, Bronchoalveolar Lavage Fluid, Caspase 3 metabolism, Cell Survival drug effects, Disease Models, Animal, Eosinophils drug effects, Fluorescent Antibody Technique, GATA3 Transcription Factor metabolism, Leukocyte Count, Male, Mice, NF-KappaB Inhibitor alpha metabolism, NF-kappa B metabolism, Peptide Fragments pharmacology, Proto-Oncogene Mas, Proto-Oncogene Proteins metabolism, Receptors, G-Protein-Coupled metabolism, Angiotensin I metabolism, Asthma immunology, Asthma metabolism, Eosinophils immunology, Eosinophils metabolism, Peptide Fragments metabolism
- Abstract
Defective apoptosis of eosinophils, the main leukocyte in the pathogenesis of asthma, and delay in its removal lead to lung damage and loss of pulmonary function due to failure in the resolution of inflammation. Here, we investigated the ability of angiotensin-(1-7) [Ang-(1-7)], a pivotal peptide of the renin-angiotensin system, to promote resolution of an allergic lung inflammatory response. Balb/c mice were sensitized and challenged with ovalbumin and treated with Ang-(1-7) at the peak of the inflammatory process. Bronchoalveolar lavage (BAL) fluid and lungs were collected 24 h after treatment. Different lung lobes were processed for histology to evaluate inflammatory cell infiltration, airway and pulmonary remodeling, total collagen staining, and measurements of (i) collagen I and III mRNA expression by qRT-PCR; (ii) ERK1/2, IκB-α, and GATA3 protein levels by Western blotting; and (iii) eosinophilic peroxidase activity. Total number of inflammatory cells, proportion of apoptotic eosinophils and immunofluorescence for caspase 3 and NF-κB in leukocytes were evaluated in the BAL. Mas receptor immunostaining was evaluated in mouse and human eosinophils. Engulfment of human polimorphonuclear cells by macrophages, efferocytosis, was evaluated in vivo . Ang-(1-7) reduced eosinophils in the lung and in the BAL, increased the number of apoptotic eosinophils, shown by histology criteria and by increase in caspase 3 immunostaining. Furthermore, Ang-(1-7) decreased NF-kB immunostaining in eosinophils, reduced GATA3, ERK1/2, and IκB-α expression in the lung and decreased pulmonary remodeling and collagen deposition. Importantly, Ang-(1-7) increased efferocytosis. Our results demonstrate, for the first time, Ang-(1-7) activates events that are crucial for resolution of the inflammatory process of asthma and promotion of the return of lung homeostasis, indicating Ang-(1-7) as novel endogenous inflammation-resolving mediator.
- Published
- 2018
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35. The ACE2/Angiotensin-(1-7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7).
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Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, and Campagnole-Santos MJ
- Subjects
- Angiotensin-Converting Enzyme 2, Animals, Humans, Proto-Oncogene Mas, Signal Transduction, Angiotensin I metabolism, Brain metabolism, Peptide Fragments metabolism, Peptidyl-Dipeptidase A metabolism, Proto-Oncogene Proteins metabolism, Receptors, G-Protein-Coupled metabolism, Renin-Angiotensin System
- Abstract
The renin-angiotensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions throughout the body. The classical view of this system saw it as a sequence of many enzymatic steps that culminate in the production of a single biologically active metabolite, the octapeptide angiotensin (ANG) II, by the angiotensin converting enzyme (ACE). The past two decades have revealed new functions for some of the intermediate products, beyond their roles as substrates along the classical route. They may be processed in alternative ways by enzymes such as the ACE homolog ACE2. One effect is to establish a second axis through ACE2/ANG-(1-7)/MAS, whose end point is the metabolite ANG-(1-7). ACE2 and other enzymes can form ANG-(1-7) directly or indirectly from either the decapeptide ANG I or from ANG II. In many cases, this second axis appears to counteract or modulate the effects of the classical axis. ANG-(1-7) itself acts on the receptor MAS to influence a range of mechanisms in the heart, kidney, brain, and other tissues. This review highlights the current knowledge about the roles of ANG-(1-7) in physiology and disease, with particular emphasis on the brain.
- Published
- 2018
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36. Chronic allergic pulmonary inflammation is aggravated in angiotensin-(1-7) Mas receptor knockout mice.
- Author
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Magalhães GS, Rodrigues-Machado MG, Motta-Santos D, Alenina N, Bader M, Santos RA, Barcelos LS, and Campagnole-Santos MJ
- Subjects
- Animals, Bronchoalveolar Lavage Fluid, Cytokines metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Hypersensitivity physiopathology, Lung metabolism, Lung pathology, Lung physiopathology, Mice, Knockout, Physical Conditioning, Animal, Pneumonia physiopathology, Proto-Oncogene Mas, Swimming, Angiotensin I metabolism, Hypersensitivity complications, Hypersensitivity metabolism, Peptide Fragments metabolism, Pneumonia complications, Pneumonia metabolism, Proto-Oncogene Proteins metabolism, Receptors, G-Protein-Coupled metabolism
- Abstract
The angiotensin-(1-7) [ANG-(1-7)]/Mas receptor pathway is currently recognized as a counterbalancing mechanism of the renin-angiotensin system in different pathophysiological conditions. We have previously described that treatment with ANG-(1-7) attenuates lung inflammation and remodeling in an experimental model of asthma. In the present study, we investigated whether lack of the Mas receptor could alter the inflammatory response in a model of chronic allergic lung inflammation induced by ovalbumin (OVA). Mas receptor wild-type (MasWT) and knockout (MasKO) mice were subjected to four doses of OVA (20 μg/mice ip) with a 14-day interval. At the 21st day, nebulization with OVA (1%) was started, three times per week until the 46th day. Control groups received saline (0.9% ip) and were nebulized with saline (0.9%). MasWT-OVA developed a modest inflammatory response and minor pulmonary remodeling to OVA challenge. Strikingly, MasKO-OVA presented a significant increase in inflammatory cell infiltrate, increase in extracellular matrix deposition, increase in thickening of the alveolar parenchyma, increase in thickening of the smooth muscle layer of the pulmonary arterioles, increase in proinflammatory cytokine and chemokine levels in the lungs, characteristic of chronic asthma. Additionally, MasKO-OVA presented an increase in ERK1/2 phosphorylation compared with MasWT-OVA. Furthermore, MasKO-OVA showed a worse performance in a test of maximum physical exercise compared with MasWT-OVA. Our study shows that effects triggered by the Mas receptor are important to attenuate the inflammatory and remodeling processes in a model of allergic lung inflammation in mice. Our data indicate that impairment of the ANG-(1-7)/Mas receptor pathway may lead to worsening of the pathophysiological changes of asthma., (Copyright © 2016 the American Physiological Society.)
- Published
- 2016
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37. Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney.
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Domenig O, Manzel A, Grobe N, Königshausen E, Kaltenecker CC, Kovarik JJ, Stegbauer J, Gurley SB, van Oyen D, Antlanger M, Bader M, Motta-Santos D, Santos RA, Elased KM, Säemann MD, Linker RA, and Poglitsch M
- Subjects
- Aminobutyrates pharmacology, Angiotensin I metabolism, Angiotensin II genetics, Angiotensin II metabolism, Angiotensin-Converting Enzyme 2, Animals, Biomarkers, Biopsy, Biphenyl Compounds pharmacology, Female, Gene Expression, Humans, Immunohistochemistry, Kidney Cortex physiology, Mice, Mice, Knockout, Neprilysin antagonists & inhibitors, Peptide Fragments metabolism, Peptidyl-Dipeptidase A genetics, Peptidyl-Dipeptidase A metabolism, Renin genetics, Renin metabolism, Kidney physiology, Neprilysin metabolism, Renin-Angiotensin System physiology
- Abstract
Cardiovascular and renal pathologies are frequently associated with an activated renin-angiotensin-system (RAS) and increased levels of its main effector and vasoconstrictor hormone angiotensin II (Ang II). Angiotensin-converting-enzyme-2 (ACE2) has been described as a crucial enzymatic player in shifting the RAS towards its so-called alternative vasodilative and reno-protective axis by enzymatically converting Ang II to angiotensin-(1-7) (Ang-(1-7)). Yet, the relative contribution of ACE2 to Ang-(1-7) formation in vivo has not been elucidated. Mass spectrometry based quantification of angiotensin metabolites in the kidney and plasma of ACE2 KO mice surprisingly revealed an increase in Ang-(1-7), suggesting additional pathways to be responsible for alternative RAS activation in vivo. Following assessment of angiotensin metabolism in kidney homogenates, we identified neprilysin (NEP) to be a major source of renal Ang-(1-7) in mice and humans. These findings were supported by MALDI imaging, showing NEP mediated Ang-(1-7) formation in whole kidney cryo-sections in mice. Finally, pharmacologic inhibition of NEP resulted in strongly decreased Ang-(1-7) levels in murine kidneys. This unexpected new role of NEP may have implications for the combination therapy with NEP-inhibitors and angiotensin-receptor-blockade, which has been shown being a promising therapeutic approach for heart failure therapy.
- Published
- 2016
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38. Effects of ACE2 deficiency on physical performance and physiological adaptations of cardiac and skeletal muscle to exercise.
- Author
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Motta-Santos D, Dos Santos RA, Oliveira M, Qadri F, Poglitsch M, Mosienko V, Kappes Becker L, Campagnole-Santos MJ, M Penninger J, Alenina N, and Bader M
- Subjects
- Angiotensin-Converting Enzyme 2, Angiotensins blood, Animals, Exercise, Exercise Test, Humans, Male, Mice, Mice, Inbred C57BL, Myocardium, Adaptation, Physiological, Heart physiology, Muscle, Skeletal physiology, Peptidyl-Dipeptidase A deficiency
- Abstract
The renin-angiotensin system (RAS) is related to physiological adaptations induced by exercise. Angiotensin-converting enzyme (ACE) 2 is a major regulator of the RAS in tissues, as it metabolizes angiotensin (Ang) II to Ang-(1-7). The aim of this study was to determine the effects of ACE2 deficiency on physical performance and physiological adaptations induced by voluntary running. Physical performance, body composition and plasma angiotensin levels, as well as tissue morphology and gene expression of RAS components in the left ventricle (LV) and skeletal muscle (gastrocnemius), were evaluated in ACE2-deficient (ACE2(-/y)) and wild-type (ACE2(+/y)) mice after 6 weeks of voluntary wheel running. ACE2(-/y) mice run less than ACE2(+/y) mice (19±4.7 vs. 26±12.6 revolutions per day × 100, P<0.01). The ACE2(+/y) group presented a lower fat mass (15±1.1%) and higher muscle mass (76.6±1.6%) after 6 weeks of voluntary running compared with the sedentary control group (fat mass: 18.3±2.1%; muscle mass: 72.7±2.2). However, no change in body composition was observed in ACE2(-/y) mice after exercise. Heart and skeletal muscle hypertrophy was observed only in trained ACE2(+/y) mice. Besides a small decrease in Ang I in ACE2(-/y) mice, plasma levels of angiotensin peptides remained unchanged by exercise or ACE2 deficiency. In the LV of trained animals, AT2 gene expression was higher in ACE2(+/y) compared with ACE2(-/y) mice. ACE2 deficiency leads to an increase in AT1 gene expression in skeletal muscle. ACE expression in soleus was increased in all exercised groups. ACE2 deficiency affects physical performance and impairs cardiac and skeletal muscle adaptations to exercise.
- Published
- 2016
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39. Contact Karate Promotes Post-Exercise Hypotension in Young Adult Males.
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Magalhaes Sales M, Victor de Sousa C, Barbosa Sampaio W, Ernesto C, Alberto Vieira Browne R, Fernando Vila Nova de Moraes J, Motta-Santos D, Rocha Moraes M, Eugene Lewis J, Gustavo Simões H, and Martins da Silva F
- Abstract
Background: Worldwide, systemic arterial hypertension is a leading cause of death and non-communicable cardiovascular disease. A major factor contributing to this disease is a sedentary lifestyle. However, physical exercise, such as martial arts, may be an option for blood pressure (BP) control. The magnitude of post-exercise hypotension is associated with a prolonged decrease in BP in normotensive and hypertensive individuals., Objectives: The present study aimed to verify the effects of a Contact Karate (CK) session on BP responses during a post-exercise recovery period in young adults., Patients and Methods: Thirty-two male CK athletes volunteered (28.2 ± 6.7 years; 77.0 ± 5.7 kg; and 176.0 ± 4.7 cm) and underwent one CK session (50 minutes) and a control session in which no exercise was performed and the individuals remain seated during the whole time. BP was measured during rest (before sessions), as well as on the 15th, 30th, 45th, and 60th minutes of the post-exercise recovery., Results: The systolic (SBP), diastolic (DBP), and mean arterial pressure (MAP) were significantly lower at the post-exercise period compared to pre-exercise rest (P < 0.05), with the largest reductions being observed at the 60th minutes of recovery [SBP (rest: 125.9 ± 4.7 vs. 60th minutes of recovery: 111.7 ± 5.4 mmHg); DBP (rest: 78.8 ± .7 vs. 60th minutes of recovery: 69.8 ± 2.7 mmHg)] and at the same periods of post-exercise recovery of the control session., Conclusions: A single CK session can promote a decrease in BP for at least 60 minutes after performing this type of exercise in young adults.
- Published
- 2016
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40. Renal Effects and Underlying Molecular Mechanisms of Long-Term Salt Content Diets in Spontaneously Hypertensive Rats.
- Author
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Berger RC, Vassallo PF, Crajoinas Rde O, Oliveira ML, Martins FL, Nogueira BV, Motta-Santos D, Araújo IB, Forechi L, Girardi AC, Santos RA, and Mill JG
- Subjects
- Angiotensin-Converting Enzyme 2, Animals, Diet, Sodium-Restricted, Glomerular Filtration Barrier metabolism, Hypertension pathology, Hypertension urine, Intracellular Signaling Peptides and Proteins metabolism, Kidney pathology, Kidney physiopathology, Male, Membrane Proteins metabolism, Peptidyl-Dipeptidase A metabolism, Rats, Inbred SHR, Renin-Angiotensin System, Sodium Chloride, Dietary metabolism, Hypertension diet therapy, Kidney enzymology
- Abstract
Several evidences have shown that salt excess is an important determinant of cardiovascular and renal derangement in hypertension. The present study aimed to investigate the renal effects of chronic high or low salt intake in the context of hypertension and to elucidate the molecular mechanisms underlying such effects. To this end, newly weaned male SHR were fed with diets only differing in NaCl content: normal salt (NS: 0.3%), low salt (LS: 0.03%), and high salt diet (HS: 3%) until 7 months of age. Analysis of renal function, morphology, and evaluation of the expression of the main molecular components involved in the renal handling of albumin, including podocyte slit-diaphragm proteins and proximal tubule endocytic receptors were performed. The relationship between diets and the balance of the renal angiotensin-converting enzyme (ACE) and ACE2 enzymes was also examined. HS produced glomerular hypertrophy and decreased ACE2 and nephrin expressions, loss of morphological integrity of the podocyte processes, and increased proteinuria, characterized by loss of albumin and high molecular weight proteins. Conversely, severe hypertension was attenuated and renal dysfunction was prevented by LS since proteinuria was much lower than in the NS SHRs. This was associated with a decrease in kidney ACE/ACE2 protein and activity ratio and increased cubilin renal expression. Taken together, these results suggest that LS attenuates hypertension progression in SHRs and preserves renal function. The mechanisms partially explaining these findings include modulation of the intrarenal ACE/ACE2 balance and the increased cubilin expression. Importantly, HS worsens hypertensive kidney injury and decreases the expression nephrin, a key component of the slit diaphragm.
- Published
- 2015
- Full Text
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41. Role of exercise intensity on GLUT4 content, aerobic fitness and fasting plasma glucose in type 2 diabetic mice.
- Author
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Cunha VN, de Paula Lima M, Motta-Santos D, Pesquero JL, de Andrade RV, de Almeida JA, Araujo RC, Grubert Campbell CS, Lewis JE, and Simões HG
- Subjects
- Animals, Blood Glucose metabolism, Diabetes Mellitus, Type 2 physiopathology, Disease Models, Animal, Fasting blood, Insulin Resistance, Mice, Mice, Inbred C57BL, Mice, Obese, Diabetes Mellitus, Type 2 therapy, Exercise Therapy, Glucose Transporter Type 4 metabolism
- Abstract
Type 2 diabetes mellitus (T2D) results in several metabolic and cardiovascular dysfunctions, clinically characterized by hyperglycaemia due to lower glucose uptake and oxidation. Physical exercise is an effective intervention for glycaemic control. However, the effects of exercising at different intensities have not yet been addressed. The present study analysed the effects of 8 weeks of training performed at different exercise intensities on type 4 glucose transporters (GLUT4) content and glycaemic control of T2D (ob/ob) and non-diabetic mice (ob/OB). The animals were divided into six groups, with four groups being subjected either to low-intensity (ob/obL and ob/OBL: 3% body weight, three times/week/40 min) or high-intensity (ob/obH and ob/OBH: 6% body weight, three times per week per 20 min) swimming training. An incremental swimming test was performed to measure aerobic fitness. After the training intervention period, glycaemia and the content of GLUT4 were quantified. Although both training intensities were beneficial, the high-intensity regimen induced a more significant improvement in GLUT4 levels and glycaemic profile compared with sedentary controls (p < 0.05). Only animals in the high-intensity exercise group improved aerobic fitness. Thus, our study shows that high-intensity training was more effective for increasing GLUT4 content and glycaemia reduction in insulin-resistant mice, perhaps because of a higher metabolic demand imposed by this form of exercise., (Copyright © 2015 John Wiley & Sons, Ltd.)
- Published
- 2015
- Full Text
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42. Effects of prior exercise on glycemic responses following carbohydrate inges on in individuals with type 2 diabetes.
- Author
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Arsa G, Lima LCJ, Motta-Santos D, Cambri LT, Grubert Campbell CS, Lewis JE, and Simões HG
- Abstract
Background: Exercise is effective in reducing glycemia, especially when it is performed in the postprandial period. However, no consensus exists in the literature about the effect of exercise on postprandial glucose control when it is performed before carbohydrate consumption., Aims: The main aim was to determine whether 20 min of exercise performed prior to carbohydrate consumption reduces postprandial glycemic and insulinemic responses. A secondary aim was to analyze the effectiveness of short-term (10 min) exercise bout with respect to postprandial glycemia reduction., Methods: Nine individuals with type 2 diabetes (54.9 ± 1.7 years; 30.7 ± 1.8 kg/m
2 ; glycemia level of 167.0 ±10.6 mg/dL) participated in the study and underwent the following procedures: (a) an incremental test to determine the lactate threshold; (b) an exercise session for 20 minutes at moderate intensity (90% of the lactate threshold); and c) a control session. The last two sessions were randomized, and the participants were monitored during 135 minutes of post-exercise recovery. A standard meal was consumed two hours before the experimental procedures started. A dextrose solution was administered at 45 minutes of post-exercise recovery while monitoring glucose and insulin concentrations. At 135 min of post-exercise recovery, eight of the participants performed an additional 10-min exercise bout following induced hyperglycemia., Results: Exercise reduced glycemia (-46.6 ± 7.9 mg/dL) and the insulin/glucose ratio (from 1.73 ± 0.59 to 0.93 ± 0.22 µU/mL/mmol/L) during the first 45 minutes of post-exercise recovery. Glycemia was significantly increased after carbohydrate consumption, reaching its peak value at 105 minutes of post-exercise recovery (261.8 ± 15.8 mg/dL) or control (281.3 ± 13.4 mg/dL). There was no effect of the previous exercise in attenuating glycemia or reducing the area under the curve for glucose and insulin after carbohydrate consumption. However, the effectiveness of exercise in reducing glycemia was shown again when it was performed at the end of the experimental session, even in case of only a 10-min exercise (reduction of -44.5 ± 4.9 mg/dL)., Conclusions: Twenty minutes of moderate exercise does not alter the kinetics or the area under the curve in terms of glycemia and insulinemia after subsequent carbohydrate consumption. However, moderate exercise, even if performed for only 10-20 minutes, is effective in reducing postprandial glycemia in individuals with type 2 diabetes., Relevance for Patients: Moderate-intensity exercise, even of short duration, may benefit individuals with type 2 diabetes on blood glucose control. A fast reduction in postprandial glycemia can be obtained with only ten minutes of exercise that, in turn, may ameliorate some of complications associated with the disease., Competing Interests: The authors have no conflicts of interest to disclose.- Published
- 2015
43. Effects of aerobic exercise intensity on 24-h ambulatory blood pressure in individuals with type 2 diabetes and prehypertension.
- Author
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Karoline de Morais P, Sales MM, Alves de Almeida J, Motta-Santos D, Victor de Sousa C, and Simões HG
- Abstract
[Purpose] To verify the effects of different intensities of aerobic exercise on 24-hour ambulatory blood pressure (BP) responses in individuals with type 2 diabetes mellitus (T2D) and prehypertension. [Subjects and Methods] Ten individuals with T2D and prehypertension (55.8 ± 7.7 years old; blood glucose 133.0 ± 36.7 mg·dL(-1) and awake BP 130.6 ± 1.6/ 80.5 ± 1.8 mmHg) completed three randomly assigned experiments: non-exercise control (CON) and exercise at moderate (MOD) and maximal (MAX) intensities. Heart rate (HR), BP, blood lactate concentrations ([Lac]), oxygen uptake (VO2), and rate of perceived exertion (RPE) were measured at rest, during the experimental sessions, and during the 60 min recovery period. After this period, ambulatory blood pressure was monitored for 24 h. [Results] The results indicate that [Lac] (MAX: 6.7±2.0 vs. MOD: 3.8±1.2 mM), RPE (MAX: 19±1.3 vs. MOD: 11±2.3) and VO2peak (MAX: 20.2±4.1 vs. MOD: 14.0±3.0 mL·kg(-1)·min(-1)) were highest following the MAX session. Compared with CON, only MAX elicited post-exercise BP reduction that lasted for 8 h after exercise and during sleep. [Conclusion] A single session of aerobic exercise resulted in 24 h BP reductions in individuals with T2D, especially while sleeping, and this reduction seems to be dependent on the intensity of the exercise performed.
- Published
- 2015
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44. Type 2 diabetes elicits lower nitric oxide, bradykinin concentration and kallikrein activity together with higher DesArg(9)-BK and reduced post-exercise hypotension compared to non-diabetic condition.
- Author
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Simões HG, Asano RY, Sales MM, Browne RA, Arsa G, Motta-Santos D, Puga GM, Lima LC, Campbell CS, and Franco OL
- Subjects
- Blood Glucose, Blood Pressure, Bradykinin analogs & derivatives, Case-Control Studies, Exercise, Female, Humans, Male, Risk Factors, Bradykinin blood, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 physiopathology, Nitric Oxide blood, Plasma Kallikrein, Post-Exercise Hypotension
- Abstract
This study compared the plasma kallikrein activity (PKA), bradykinin concentration (BK), DesArg(9)-BK production, nitric oxide release (NO) and blood pressure (BP) response after moderate-intensity aerobic exercise performed by individuals with and without type 2 diabetes. Ten subjects with type 2 diabetes (T2D) and 10 without type 2 diabetes (ND) underwent three sessions: 1) maximal incremental test on cycle ergometer to determine lactate threshold (LT); 2) 20-min of constant-load exercise on cycle ergometer, at 90% LT and; 3) control session. BP and oxygen uptake were measured at rest and at 15, 30 and 45 min post-exercise. Venous blood samples were collected at 15 and 45 minutes of the recovery period for further analysis of PKA, BK and DesArg(9)-BK. Nitrite plus nitrate (NOx) was analyzed at 15 minutes post exercise. The ND group presented post-exercise hypotension (PEH) of systolic blood pressure and mean arterial pressure on the 90% LT session but T2D group did not. Plasma NOx increased ~24.4% for ND and ~13.8% for T2D group 15 min after the exercise session. Additionally, only ND individuals showed increases in PKA and BK in response to exercise and only T2D group showed increased DesArg(9)-BK production. It was concluded that T2D individuals presented lower PKA, BK and NOx release as well as higher DesArg(9)-BK production and reduced PEH in relation to ND participants after a single exercise session.
- Published
- 2013
- Full Text
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45. Discovery and characterization of alamandine: a novel component of the renin-angiotensin system.
- Author
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Lautner RQ, Villela DC, Fraga-Silva RA, Silva N, Verano-Braga T, Costa-Fraga F, Jankowski J, Jankowski V, Sousa F, Alzamora A, Soares E, Barbosa C, Kjeldsen F, Oliveira A, Braga J, Savergnini S, Maia G, Peluso AB, Passos-Silva D, Ferreira A, Alves F, Martins A, Raizada M, Paula R, Motta-Santos D, Klempin F, Pimenta A, Alenina N, Sinisterra R, Bader M, Campagnole-Santos MJ, and Santos RA
- Subjects
- Angiotensin I physiology, Angiotensin II analogs & derivatives, Angiotensin II chemistry, Angiotensin II physiology, Angiotensin-Converting Enzyme 2, Animals, Antihypertensive Agents isolation & purification, CHO Cells, Cell Line, Tumor, Cricetinae, Cricetulus, Humans, Male, Oligopeptides physiology, Peptide Fragments physiology, Peptidyl-Dipeptidase A physiology, Proto-Oncogene Mas, Proto-Oncogene Proteins chemistry, Proto-Oncogene Proteins physiology, Rats, Rats, Inbred F344, Rats, Inbred SHR, Receptors, G-Protein-Coupled chemistry, Receptors, G-Protein-Coupled physiology, Angiotensin I chemistry, Antihypertensive Agents chemistry, Antihypertensive Agents pharmacology, Drug Discovery methods, Oligopeptides chemistry, Peptide Fragments chemistry, Renin-Angiotensin System physiology
- Abstract
Rationale: The renin-angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte, and water balance. Here, we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of angiotensin-converting enzyme-2 angiotensin A or directly from angiotensin-(1-7)., Objective: To characterize a novel component of the RAS, alamandine., Methods and Results: Using mass spectrometry we observed that alamandine circulates in human blood and can be formed from angiotensin-(1-7) in the heart. Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. Binding of alamandine to Mas-related G-protein-coupled receptor, member D is blocked by D-Pro(7)-angiotensin-(1-7), the Mas-related G-protein-coupled receptor, member D ligand β-alanine and PD123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/β-hydroxypropyl cyclodextrin produced a long-term antihypertensive effect in spontaneously hypertensive rats and antifibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or antiproliferative effect in human tumoral cell lines., Conclusions: The identification of these 2 novel components of the RAS, alamandine and its receptor, provides new insights for the understanding of the physiological and pathophysiological role of the RAS and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders.
- Published
- 2013
- Full Text
- View/download PDF
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