Serum Levels of BDNF in Cardiovascular Protection and in Response to Exercise. / Níveis Séricos do BDNF na Proteção Cardiovascular e em Resposta ao Exercício.

Cardiovascular disease (CVD) is currently the leading cause of death in Brazil and worldwide. In 2016, CVD accounted for more than 17 million deaths, representing 31% of all deaths globally. Molecular and genetic mechanisms may be involved in vascular protection and should be considered in new therapeutic approaches. In this sense, recent studies have reported that brain-derived neurotrophic factor (BDNF) is reduced in individuals predisposed to develop CVD, and that aerobic physical training increases the amounts of circulating BDNF. BDNF is a neurotrophin found at high concentrations in the hippocampus and cerebral cortex and is considered a key molecule for the maintenance of synaptic plasticity and survival of neuronal cells. In addition to neuronal plasticity, BDNF is also important in vascular function, promoting angiogenesis through the regulation of reactive oxygen species (ROS). However, a variant of the BDNF gene in humans, the Val66Met polymorphism (substitution of the amino acid valine for a methionine at position 66 of the codon), occurring in 20-30% of the Caucasian population, may affect plasma BDNF concentrations and its activity in all peripheral tissues containing tyrosine kinase B receptors (TrkB), such as the endothelium. Thus, we will present a discussion about the role of serum BDNF levels in cardiovascular protection, Val66Met genetic variant in vascular reactivity and the effect of physical exercise.

As doenças cardiovasculares (DCV) são atualmente a maior causa de morte no Brasil e no mundo. Em 2016 as DCV foram responsáveis por mais de 17 milhões de mortes, representando 31% de todas as mortes em nível global. Mecanismos moleculares e genéticos podem estar envolvidos na proteção cardiovascular e devem ser considerados nas novas abordagens terapêuticas. Nesse sentido, recentes estudos têm relatado que o Fator Neurotrófico Derivado do Encéfalo (Brain-Derived Neurotrophic Factor, BDNF) está reduzido em indivíduos predispostos a desenvolverem DCV, e que o treinamento físico aeróbio aumenta as quantidades de BDNF circulante. O BDNF é uma neurotrofina encontrada em altas concentrações no hipocampo e córtex cerebral, sendo considerada molécula-chave na manutenção da plasticidade sináptica e na sobrevivência das células neuronais. Além da plasticidade neuronal, BDNF também é importante na função vascular, promovendo angiogênese por meio da regulação por espécies reativas de oxigênio (ROS). Entretanto, uma variante do gene do BDNF em humanos, o polimorfismo Val66Met (substituição do aminoácido valina por uma metionina na posição 66 do códon), que ocorre em 20-30% da população caucasiana, pode afetar as concentrações de BDNF no plasma e sua atividade em todos os tecidos periféricos contendo receptores tirosina quinase B (TrkB), como o endotélio. De fato, recentemente observamos que o polimorfismo Val66Met prejudica a reatividade vascular e o BDNF circulante em resposta ao treinamento físico. Dessa forma, apresentaremos a seguir uma discussão sobre os níveis séricos de BDNF na proteção cardiovascular, a variante genética Val66Met na reatividade vascular e o efeito do exercício físico.

Níveis Séricos do BDNF na Proteção Cardiovascular e em Resposta ao Exercício / Serum Levels of BDNF in Cardiovascular Protection and in Response to Exercise

Resumo As doenças cardiovasculares (DCV) são atualmente a maior causa de morte no Brasil e no mundo. Em 2016 as DCV foram responsáveis por mais de 17 milhões de mortes, representando 31% de todas as mortes em nível global. Mecanismos moleculares e genéticos podem estar envolvidos na proteção cardiovascular e devem ser considerados nas novas abordagens terapêuticas. Nesse sentido, recentes estudos têm relatado que o Fator Neurotrófico Derivado do Encéfalo (Brain-Derived Neurotrophic Factor, BDNF) está reduzido em indivíduos predispostos a desenvolverem DCV, e que o treinamento físico aeróbio aumenta as quantidades de BDNF circulante. O BDNF é uma neurotrofina encontrada em altas concentrações no hipocampo e córtex cerebral, sendo considerada molécula-chave na manutenção da plasticidade sináptica e na sobrevivência das células neuronais. Além da plasticidade neuronal, BDNF também é importante na função vascular, promovendo angiogênese por meio da regulação por espécies reativas de oxigênio (ROS). Entretanto, uma variante do gene do BDNF em humanos, o polimorfismo Val66Met (substituição do aminoácido valina por uma metionina na posição 66 do códon), que ocorre em 20-30% da população caucasiana, pode afetar as concentrações de BDNF no plasma e sua atividade em todos os tecidos periféricos contendo receptores tirosina quinase B (TrkB), como o endotélio. De fato, recentemente observamos que o polimorfismo Val66Met prejudica a reatividade vascular e o BDNF circulante em resposta ao treinamento físico. Dessa forma, apresentaremos a seguir uma discussão sobre os níveis séricos de BDNF na proteção cardiovascular, a variante genética Val66Met na reatividade vascular e o efeito do exercício físico.

Abstract Cardiovascular disease (CVD) is currently the leading cause of death in Brazil and worldwide. In 2016, CVD accounted for more than 17 million deaths, representing 31% of all deaths globally. Molecular and genetic mechanisms may be involved in vascular protection and should be considered in new therapeutic approaches. In this sense, recent studies have reported that brain-derived neurotrophic factor (BDNF) is reduced in individuals predisposed to develop CVD, and that aerobic physical training increases the amounts of circulating BDNF. BDNF is a neurotrophin found at high concentrations in the hippocampus and cerebral cortex and is considered a key molecule for the maintenance of synaptic plasticity and survival of neuronal cells. In addition to neuronal plasticity, BDNF is also important in vascular function, promoting angiogenesis through the regulation of reactive oxygen species (ROS). However, a variant of the BDNF gene in humans, the Val66Met polymorphism (substitution of the amino acid valine for a methionine at position 66 of the codon), occurring in 20-30% of the Caucasian population, may affect plasma BDNF concentrations and its activity in all peripheral tissues containing tyrosine kinase B receptors (TrkB), such as the endothelium. Thus, we will present a discussion about the role of serum BDNF levels in cardiovascular protection, Val66Met genetic variant in vascular reactivity and the effect of physical exercise.

Aerobic exercise training differentially affects ACE C- and N-domain activities in humans: Interactions with ACE I/D polymorphism and association with vascular reactivity.

INTRODUCTION: Previous studies have linked angiotensin-converting enzyme ( ACE) insertion (I)/deletion (D) polymorphism (II, ID and DD) to physical performance. Moreover, ACE has two catalytic domains: NH2 (N) and COOH (C) with distinct functions, and their activity has been found to be modulated by ACE polymorphism. The aim of the present study is to investigate the effects of the interaction between aerobic exercise training (AET) and ACE I/D polymorphism on ACE N- and C-domain activities and vascular reactivity in humans. MATERIALS AND METHODS: A total of 315 pre-selected healthy males were genotyped for II, ID and DD genotypes. Fifty completed the full AET (II, n = 12; ID, n = 25; and DD, n = 13), performed in three 90-minute sessions weekly, in the four-month exercise protocol. Pre- and post-training resting heart rate (HR), peak O2 consumption (VO2 peak), mean blood pressure (MBP), forearm vascular conduction (FVC), total circulating ACE and C- and N-domain activities were assessed. One-way ANOVA and two -way repeated-measures ANOVA were used. RESULTS: In pre-training, all variables were similar among the three genotypes. In post-training, a similar increase in FVC (35%) was observed in the three genotypes. AET increased VO2 peak similarly in II, ID and DD (49±2 vs. 57±1; 48±1 vs. 56±3; and 48±5 vs. 58±2 ml/kg/min, respectively). Moreover, there were no changes in HR and MBP. The DD genotype was also associated with greater ACE and C-domain activities at pre- and post-training when compared to II. AET decreased similarly the total ACE and C-domain activities in all genotypes, while increasing the N-domain activity in the II and DD genotypes. However, interestingly, the measurements of N-domain activity after training indicate a greater activity than the other genotypes. These results suggest that the vasodilation in response to AET may be associated with the decrease in total ACE and C-domain activities, regardless of genotype, and that the increase in N-domain activity is dependent on the DD genotype. CONCLUSIONS: AET differentially affects the ACE C- and N-domain activities, and the N-domain activity is dependent on ACE polymorphism.

PBMCs express a transcriptome signature predictor of oxygen uptake responsiveness to endurance exercise training in men.

Peripheral blood cells are an accessible environment in which to visualize exercise-induced alterations in global gene expression patterns. We aimed to identify a peripheral blood mononuclear cell (PBMC) signature represented by alterations in gene expression, in response to a standardized endurance exercise training protocol. In addition, we searched for molecular classifiers of the variability in oxygen uptake (V̇o2). Healthy untrained policemen recruits (n = 13, 25 ± 3 yr) were selected. Peak V̇o2 (measured by cardiopulmonary exercise testing) and total RNA from PBMCs were obtained before and after 18 wk of running endurance training (3 times/wk, 60 min). Total RNA was used for whole genome expression analysis using Affymetrix GeneChip Human Gene 1.0 ST. Data were normalized by the robust multiarray average algorithm. Principal component analysis was used to perform correlations between baseline gene expression and V̇o2peak. A set of 211 transcripts was differentially expressed (ANOVA, P < 0.05 and fold change > 1.3). Functional enrichment analysis revealed that transcripts were mainly related to immune function, cell cycle processes, development, and growth. Baseline expression of 98 and 53 transcripts was associated with the absolute and relative V̇o2peak response, respectively, with a strong correlation (r > 0.75, P < 0.01), and this panel was able to classify the 13 individuals according to their potential to improve oxygen uptake. A subset of 10 transcripts represented these signatures to a similar extent. PBMCs reveal a transcriptional signature responsive to endurance training. Additionally, a baseline transcriptional signature was associated with changes in V̇o2peak. Results might illustrate the possibility of obtaining molecular classifiers of endurance capacity changes through a minimally invasive blood sampling procedure.

Expressão e seleção de microRNAs no músculo esquelético de homens saudáveis submetidos ao treinamento físico aeróbio / MicroRNA-206 skeletal muscle-specific modulates pattern of expression in myogenesis in response to endurance training in human

O treinamento físico aeróbio (TFA) foi estabelecido como uma conduta importante capaz de alterar a musculatura esquelética humana. Os microRNAs (miRs) surgiram como importantes reguladores de processos biológicos, modulando a expressão de genes pós-transcricionalmente. Os myomiRs são miRs específico do músculo esquelético, em especial o miR-206, que é necessário para uma eficiente regeneração das fibras musculares esqueléticas. No entanto, a expressão do miR-206 em resposta ao TFA, não é completamente comprendida. O objetivo do presente estudo foi determinar os padrões de expressão dos myomiRs na musculatura esquelética humana. Doze voluntários saudáveis foram biopsiados pré e pós-treinamento físico. As expressões gênicas e proteicas envolvidas na miogênese foram observadas, incluindo; PAX-7, MYF5, MYOD, MRF4, MYOG, CD31 e FSTL. Além disso, a freqüência cardíaca (FC), pressão arterial média (PAM), consumo máximo de oxigênio (VO2max), fluxo sanguineo no antebraço (FSA) e condutância vascular no antebraço (CVA), foram avaliados. Ademais, os myomiRs foram analisados por PCR em tempo real. O treinamento físico aeróbio foi realizado durante 16 semanas. Todas as variáveis foram reavaliadas após o treinamento. Os indivíduos apresentaram um aumento nas expressões dos myomiRs, em especial do miRs-206 de 93%. Estas alterações foram acompanhadas por aumento nas expressões dos genes; PAX-7, MYOD, MYF5, MFR4, MYOG e FSTL, respectivamente. No entanto, quando analisamos as expressões proteicas, houve redução na FSTL e PAX-7, de 24%, 29%, respectivamente. Além disso, em MYOD, CD31, MYOG e MHC houve aumentos de 21%, 41%, 79% e 94%, respectivamente. Ademais, houve uma diminuição na frequência cardíaca de reposuso de 12,5% e aumentos no VO2pico, FSA e CVA de 14,1%, 68%, 63%, respectivamente. Estes resultados sugerem que em indivíduos saudáveis o miRs-206 é altamente expresso após o treinamento físico aeróbio, dessa forma,...

Endurance training (ET) has been established as an important phenotype capable of altering the human skeletal muscle. MicroRNAs (miRs) have emerged as important regulators of numerous biological processes by modulating gene expression at the post-transcriptional level. The myomiRs are particulars miRs of muscles, in special skeletal muscle-specific miR-206 that is required for efficient regeneration muscle fiber. However, the expression of myomiRs and in special miR-206 in response to ET in human skeletal muscle is not completely understood. Twelve healthy volunteers were biopsied pre and post period endurance training. Most of the biological processes involved in the transcriptional regulation were observed, including PAX-7, MYF5, MYOD, MRF4, MYOG, CD31 and FSTL, analyzed by real time PCR. Moreover, heart rate (HR), mean blood pressure (MBP), maximal exercise capacity (VO2peak) forearm blood flow (FBF) and forearm vascular conductance (FVC) were evaluated. The myomiRs levels analyzed by real-time PCR. Endurance training was performed for 16 weeks. All variables were re-assessed following completion of the training period. After endurance training, the individuals showed an increase in myomiRs, in special of 93% in human skeletal muscle in miRNA-206 levels. These alterations were accompanied by increase in PAX-7, MYOD, MYF5, MFR4, MYOG and FSTL gene expression, respectively. However, when analyzed by western blot comparing pre and post period there were reduction in FSTL of 24% and PAX-7 of 29% in protein levels, but in MYOD, CD31, MYOG and MHC there were increase of 21%, 41%, 79% and 94% in protein levels, respectively. In addition, there was a decrease in hear rate of 12.5% and increases in VO2peak of 14.1%, FBF of 68% and FVC of 63%.These results suggest that in healthy individuals the miR-206 is highly expressed after endurance training, thus modulating locally important parts in myogenic processes in humans.

Vascular reactivity and ACE activity response to exercise training are modulated by the +9/-9 bradykinin B2 receptor gene functional polymorphism.

The bradykinin receptor B2 (BDKRB2) gene +9/-9 polymorphism has been associated with higher gene transcriptional activity, and characteristics of cardiovascular phenotypes and physical performance. We hypothesized that vasodilation and ACE activity response to exercise training is modulated by BDKRB2 gene. We genotyped 71 healthy volunteers were genotyped for the BDKRB2 gene polymorphism. Heart rate (HR), mean blood pressure (MBP), and forearm blood flow (FBF) were evaluated. Angiotensin-I converting enzyme (ACE) activity was measured by fluorescence. Aerobic training was performed for 16 wk. All variables were reassessed after completion of the training period. In pretraining period, HR, MBP, FBF, and forearm vascular conductance (FVC) were similar among all genotypes. After physical training, the FBF and the FVC response during handgrip exercise such as area under the curve were higher in -9/-9 carriers than the other two groups. However, there were no changes in HR and MBP for all three groups. In addition, in posttraining period the decrease in ACE activity was higher in the -9/-9 group than the other two groups. These results suggest that reflex muscle vasodilation and ACE activity in response to exercise training are modulated by BDKRB2 gene +9/-9 polymorphism in healthy individuals.