Epigenetic control of exercise training-induced cardiac hypertrophy by miR-208.

Aerobic exercise-induced cardiac hypertrophy (CH) is a physiological response involving accurate orchestration of gene and protein expression of contractile and metabolic components. The microRNAs: miR-208a, miR-208b and miR-499 are each encoded by a myosin gene and thus are also known as 'MyomiRs', regulating several mRNA targets that in turn regulate CH and metabolic pathways. To understand the role of myomiRs in the fine-tuning of cardiac myosin heavy chain (MHC) isoform expression by exercise training-induced physiological hypertrophy, Wistar rats were subjected to two different swim training protocols. We observed that high-volume swim training (T2), improved cardiac diastolic function, induced CH and decreased the expression of miR-208a and miR-208b Consequently, the increased expression of their targets, sex determining region y-related transcription factor 6 (Sox6), Med13, Purß, specificity proteins (Sp)/Krüppel-like transcription factor 3 (SP3) and HP1ß (heterochromatin protein 1ß) was more prominent in T2, thus converging to modulate cardiac metabolic and contractile adaptation by exercise training, with an improvement in the α-MHC/ß-MHC ratio, bypassing the increase in PPARß and histone deacetylase (HDAC) class I and II regulation. Altogether, we conclude that high-volume swim training finely assures physiological cardiac remodelling by epigenetic regulation of myomiRs, because inhibition of miR-208a and miR-208b increases the expression of their target proteins and stimulates the interaction among metabolic, contractile and epigenetic genes.

Cardiac and peripheral adjustments induced by early exercise training intervention were associated with autonomic improvement in infarcted rats: role in functional capacity and mortality.

AIMS: To test the effects of early exercise training (ET) on left ventricular (LV) and autonomic functions, haemodynamics, tissues blood flows (BFs), maximal oxygen consumption (VO(2) max), and mortality after myocardial infarction (MI) in rats. METHODS AND RESULTS: Male Wistar rats were divided into: control (C), sedentary-infarcted (SI), and trained-infarcted (TI). One week after MI, TI group underwent an ET protocol (90 days, 50-70% VO(2) max). Left ventricular function was evaluated non-invasively and invasively. Baroreflex sensitivity, heart rate variability, and pulse interval were measured. Cardiac output (CO) and regional BFs were determined using coloured microspheres. Infarcted area was reduced in TI (19 ± 6%) compared with SI (34 ± 5%) after ET. Exercise training improved the LV and autonomic functions, the CO and regional BF changes induced by MI, as well as increased SERCA2 expression and mRNA vascular endothelial growth factor levels. These changes brought about by ET resulted in mortality rate reduction in the TI (13%) group compared with the SI (54%) group. CONCLUSION: Early aerobic ET reduced cardiac and peripheral dysfunctions and preserved cardiovascular autonomic control after MI in trained rats. Consequently, these ET-induced changes resulted in improved functional capacity and survival after MI.

Effects of resistance training on ventricular function and hypertrophy in a rat model.

OBJECTIVE: The purpose of this study was to follow the ventricular function and cardiac hypertrophy in rats undergoing a resistance-training program for a period of 3 months. DESIGN: Forty animals were divided into two major groups: control (n=16) and resistance trained (n=24). From the resistance-trained group, 12 animals were resistance trained for 1 month and another 12 for 3 months. The resistance-training protocol was performed with 4 sets of 12 repetitions using 65% to 75% of one repetition maximum (maximum lifted weight with the exercise apparatus). METHODS: Echocardiographic analysis was performed at the beginning of the resistance-training period and at the end of each month. The repetition maximum was measured every 2 weeks. Cardiac hypertrophy was determined by echocardiography, by the absolute weight of the cardiac chambers and by histology of the left ventricle. RESULTS: Before resistance training, both groups had similar repetition maximums, ranging from 1.8-fold to 2-fold the body weight; however, at the end of the resistance-training period, the repetition maximum of the resistance-trained group was 6-fold greater than the body weight. The left ventricular mass as assessed by echocardiography was 8%, 12% and 16% larger in the resistance-trained group than in the control group in the first, second and third months, respectively. This hypertrophy showed a similar increase in the interventricular septum and in the free posterior wall mass. There was no reduction in the end-diastolic left ventricular internal diameter during the 3-month resistance-training period. Systolic function did not differ between the groups throughout the resistance-training period. CONCLUSION: Resistance training induces the development of concentric cardiac hypertrophy without ventricular dysfunction or cavity reduction. Although diastolic function was not completely investigated, we cannot exclude the possibility that resistance training results in diastolic dysfunction.

Effects of aerobic exercise training on cardiac renin-angiotensin system in an obese Zucker rat strain.

OBJECTIVE: Obesity and renin angiotensin system (RAS) hyperactivity are profoundly involved in cardiovascular diseases, however aerobic exercise training (EXT) can prevent obesity and cardiac RAS activation. The study hypothesis was to investigate whether obesity and its association with EXT alter the systemic and cardiac RAS components in an obese Zucker rat strain. METHODS: THE RATS WERE DIVIDED INTO THE FOLLOWING GROUPS: Lean Zucker rats (LZR); lean Zucker rats plus EXT (LZR+EXT); obese Zucker rats (OZR) and obese Zucker rats plus EXT (OZR+EXT). EXT consisted of 10 weeks of 60-min swimming sessions, 5 days/week. At the end of the training protocol heart rate (HR), systolic blood pressure (SBP), cardiac hypertrophy (CH) and function, local and systemic components of RAS were evaluated. Also, systemic glucose, triglycerides, total cholesterol and its LDL and HDL fractions were measured. RESULTS: The resting HR decreased (∼12%) for both LZR+EXT and OZR+EXT. However, only the LZR+EXT reached significance (p<0.05), while a tendency was found for OZR versus OZR+EXT (p = 0.07). In addition, exercise reduced (57%) triglycerides and (61%) LDL in the OZR+EXT. The systemic angiotensin I-converting enzyme (ACE) activity did not differ regardless of obesity and EXT, however, the OZR and OZR+EXT showed (66%) and (42%), respectively, less angiotensin II (Ang II) plasma concentration when compared with LZR. Furthermore, the results showed that EXT in the OZR prevented increase in CH, cardiac ACE activity, Ang II and AT2 receptor caused by obesity. In addition, exercise augmented cardiac ACE2 in both training groups. CONCLUSION: Despite the unchanged ACE and lower systemic Ang II levels in obesity, the cardiac RAS was increased in OZR and EXT in obese Zucker rats reduced some of the cardiac RAS components and prevented obesity-related CH. These results show that EXT prevented the heart RAS hyperactivity and cardiac maladaptive morphological alterations in obese Zucker rats.

Short-term diabetes attenuates left ventricular dysfunction and mortality rates after myocardial infarction in rodents.

OBJECTIVES: To investigate the effects of hyperglycemia on left ventricular dysfunction, morphometry, myocardial infarction area, hemodynamic parameters, oxidative stress profile, and mortality rate in rats that had undergone seven days of myocardial infarction. INTRODUCTION: Previous research has demonstrated that hyperglycemia may protect the heart against ischemic injury. METHODS: Male Wistar rats were divided into four groups: control-sham, diabetes-sham, myocardial infarction, and diabetes + myocardial infarction. Myocardial infarction was induced 14 days after diabetes induction. Ventricular function and morphometry, as well as oxidative stress and hemodynamic parameters, were evaluated after seven days of myocardial infarction. RESULTS: The myocardial infarction area, which was similar in the infarcted groups at the initial evaluation, was reduced in the diabetes + myocardial infarction animals (23 ± 3%) when compared with the myocardial infarction (42 ± 7%, p < 0.001) animals at the final evaluation. The ejection fraction (22%, p = 0.003), velocity of circumferential fiber shortening (30%, p = 0.001), and left ventricular isovolumetric relaxation time (26%, p = 0.002) were increased in the diabetes + myocardial infarction group compared with the myocardial infarction group. The diabetes-sham and diabetes + myocardial infarction groups displayed increased catalase concentrations compared to the control-sham and myocardial infarction groups (diabetes-sham: 32 ± 3; diabetes + myocardial infarction: 35 ± 0.7; control-sham: 12 ± 2; myocardial infarction: 16 ± 0.1 pmol min⁻¹ mg⁻¹ protein). The levels of thiobarbituric acid-reactive substances were reduced in the diabetes-sham rats compared to the control-sham rats. These positive adaptations were reflected in a reduced mortality rate in the diabetes + myocardial infarction animals (18.5%) compared with the myocardial infarction animals (40.7%, p = 0.001). CONCLUSIONS: These data suggest that short-term hyperglycemia initiates compensatory mechanisms, as demonstrated by increased catalase levels, which culminate in improvements in the ventricular response, infarcted area, and mortality rate in diabetic rats exposed to ischemic injury.

Anabolic steroid associated to physical training induces deleterious cardiac effects.

PURPOSE: Cardiac aldosterone might be involved in the deleterious effects of nandrolone decanoate (ND) on the heart. Therefore, we investigated the involvement of cardiac aldosterone, by the pharmacological block of AT1 or mineralocorticoid receptors, on cardiac hypertrophy and fibrosis. METHODS: Male Wistar rats were randomized into eight groups (n = 14 per group): Control (C), nandrolone decanoate (ND), trained (T), trained ND (TND), ND + losartan (ND + L), trained ND + losartan (TND + L), ND + spironolactone (ND + S), and trained ND + spironolactone (TND + S). ND (10 mg·kg(-1)·wk(-1)) was administered during 10 wk of swimming training (five times per week). Losartan (20 mg·kg(-1)·d(-1)) and spironolactone (10 mg·kg(-1)·d(-1)) were administered in drinking water. RESULTS: Cardiac hypertrophy was increased 10% by using ND and 17% by ND plus training (P < 0.05). In both groups, there was an increase in the collagen volumetric fraction (CVF) and cardiac collagen type III expression (P < 0.05). The ND treatment increased left ventricle-angiotensin-converting enzyme I activity, AT1 receptor expression, aldosterone synthase (CYP11B2), and 11-ß hydroxysteroid dehydrogenase 2 (11ß-HSD2) gene expression and inflammatory markers, TGFß and osteopontin. Both losartan and spironolactone inhibited the increase of CVF and collagen type III. In addition, both treatments inhibited the increase in left ventricle-angiotensin-converting enzyme I activity, CYP11B2, 11ß-HSD2, TGFß, and osteopontin induced by the ND treatment. CONCLUSIONS: We believe this is the first study to show the effects of ND on cardiac aldosterone. Our results suggest that these effects may be associated to TGFß and osteopontin. Thus, we conclude that the cardiac aldosterone has an important role on the deleterious effects on the heart induced by ND.

Nandrolone and resistance training induce heart remodeling: role of fetal genes and implications for cardiac pathophysiology.

AIMS: This study was conducted to assess the isolated and combined effects of nandrolone and resistance training on cardiac morphology, function, and mRNA expression of pathological cardiac hypertrophy markers. MAIN METHODS: Wistar rats were randomly divided into four groups and submitted to 6 weeks of treatment with nandrolone and/or resistance training. Cardiac parameters were determined by echocardiography. Heart was analyzed for collagen infiltration. Real-time RT-PCR was used to assess the pathological cardiac hypertrophy markers. KEY FINDINGS: Both resistance training and nandrolone induced cardiac hypertrophy. Nandrolone increased the cardiac collagen content, and reduced the cardiac index in non-trained and trained groups, when compared with the respective vehicle-treated groups. Nandrolone reduced the ratio of maximum early to late transmitral flow velocity in non-trained and trained groups, when compared with the respective vehicle-treated groups. Nandrolone reduced the alpha-myosin heavy chain gene expression in both non-trained and trained groups, when compared with the respective vehicle-treated groups. Training reduced the beta-myosin heavy chain gene expression in the groups treated with vehicle and nandrolone. Only the association between training and nandrolone increased the expression of the skeletal alpha-actin gene and atrial natriuretic peptide in the left ventricle. SIGNIFICANCE: This study indicated that nandrolone, whether associated with resistance training or not, induces cardiac hypertrophy, which is associated with enhanced collagen content, re-expression of fetal genes the in left ventricle, and impaired diastolic and systolic function.

Short-term diabetes attenuates left ventricular dysfunction and mortality rates after myocardial infarction in rodents

OBJECTIVES: To investigate the effects of hyperglycemia on left ventricular dysfunction, morphometry, myocardial infarction area, hemodynamic parameters, oxidative stress profile, and mortality rate in rats that had undergone seven days of myocardial infarction. INTRODUCTION: Previous research has demonstrated that hyperglycemia may protect the heart against ischemic injury. METHODS: Male Wistar rats were divided into four groups: control-sham, diabetes-sham, myocardial infarction, and diabetes + myocardial infarction. Myocardial infarction was induced 14 days after diabetes induction. Ventricular function and morphometry, as well as oxidative stress and hemodynamic parameters, were evaluated after seven days of myocardial infarction. RESULTS: The myocardial infarction area, which was similar in the infarcted groups at the initial evaluation, was reduced in the diabetes + myocardial infarction animals (23 ± 3 percent) when compared with the myocardial infarction (42 ± 7 percent, p<0.001) animals at the final evaluation. The ejection fraction (22 percent, p = 0.003), velocity of circumferential fiber shortening (30 percent, p = 0.001), and left ventricular isovolumetric relaxation time (26 percent, p = 0.002) were increased in the diabetes + myocardial infarction group compared with the myocardial infarction group. The diabetes-sham and diabetes + myocardial infarction groups displayed increased catalase concentrations compared to the control-sham and myocardial infarction groups (diabetes-sham: 32± 3; diabetes + myocardial infarction: 35± 0.7; control-sham: 12 ± 2; myocardial infarction: 16 ± 0.1 pmol min-1 mg-1 protein). The levels of thiobarbituric acid-reactive substances were reduced in the diabetes-sham rats compared to the control-sham rats. These positive adaptations were reflected in a reduced mortality rate in the diabetes + myocardial infarction animals (18.5 percent) compared with the myocardial infarction animals (40.7 percent, p = 0.001). CONCLUSIONS: These data suggest that short-term hyperglycemia initiates compensatory mechanisms, as demonstrated by increased catalase levels, which culminate in improvements in the ventricular response, infarcted area, and mortality rate in diabetic rats exposed to ischemic injury.

Treinamento físico aeróbio previne à hipertrofia cardíaca patológica e melhora a função diastólica em ratos Zucker obesos / Aerobic exercise training revert pathologic cardiac hypertrophy and improves the diastolic function in obese Zucker rats

A obesidade é uma patologia diretamente relacionada com o desenvolvimento de doenças cardiovasculares. Por outro lado, o treinamento físico aeróbio atenua o desenvolvimento da obesidade e promove benefícios cardíacos em obesos. Dessa forma, nosso objetivo foi investigar se a obesidade altera a função cardíaca e se sua associação com o treinamento físico aeróbio promove melhora na função cardíaca em ratos Zucker obesos. Os ratos Zucker foram divididos da seguinte forma: grupo magro (GM), grupo obeso (GO), grupo magro treinado (GMTR) e grupo obeso treinado (GOTR). O protocolo de treinamento aeróbio de natação foi realizado por um período de 10 semanas com cinco sessões semanais de 60 minutos de duração. A frequência cardíaca de repouso, a pressão arterial sistólica, a hipertrofia e função cardíaca foram avaliadas no final do período de treinamento físico. Ambos os grupos treinados apresentaram uma queda de 12 por cento da frequência cardíaca de repouso, quando comparado com seus respectivos controles. Ainda, nossos resultados demonstraram que o treinamento aeróbio reduziu o aumento da massa cardíaca em 13 por cento e melhorou a função diastólica na obesidade em 43 por cento. Em conclusão, nossos dados demonstraram que o treinamento físico aeróbio reverteu os prejuízos cardíacos causados pela obesidade.

Obesity is profoundly involved in cardiovascular diseases. On the other hand, aerobic exercise training (EXT) attenuates obesity and promotes cardiac benefits in obese individuals. Therefore, the aim of this study was to investigate if obesity alters the cardiac function and whether its association with exercise training can improve cardiac function in an obese Zucker rat strain. The rats were divided in the following groups: Lean Zucker rats (LZR); lean Zucker rats plus exercise training (LZR+EXT); obese Zucker rat (OZR) and obese Zucker rat plus exercise training (OZR+EXT). EXT consisted of 10 weeks swimming sessions of 60 min, 5 days/week. At the end of the training protocol we evaluated heart rate (HR), systolic blood pressure (SBP), cardiac hypertrophy (CH) and function. The trained groups LZR+EXT and OZR+EXT showed a 12 percent lower resting HR when compared with theirs respective controls. In addition, our results showed that exercise training reduced the cardiac mass by 13 percent and improved the diastolic function by 43 percent in the obese trained group when compared with the obese untrained. In conclusion, aerobic exercise training reverts the cardiac injuries in obese Zucker rats.

A associação de esteroide anabolizante ao treinamento físico aeróbio leva a alterações morfológicas cardíacas e perda de função ventricular em ratos / Association between anabolic steroids and aerobic physical training leads to cardiac morphological alterations and loss of ventricular function in rats

INTRODUÇÃO: O esteroide anabolizante (EA) associado ao treinamento físico induz mudança da hipertrofia cardíaca (HC) fisiológica para patológica. Entretanto, esses trabalhos foram realizados com atletas de força, sendo os efeitos do EA associados ao treinamento aeróbio poucos conhecidos. Com isso, o objetivo do estudo foi avaliar os efeitos do treinamento aeróbio e dos EA sobre a estrutura e função cardíaca. MÉTODOS: Foram utilizados 28 ratos Wistar divididos em quatro grupos: sedentários controle (SC), sedentários anabolizante (SA), treinados controle (TC) e treinado anabolizante (TA). O EA foi administrado duas vezes por semana (10mg/kg/ semana). O treinamento físico de natação foi realizado durante 10 semanas, cinco sessões semanais. Foram avaliadas a pressão arterial e frequência cardíaca por pletismografia de cauda, função ventricular por ecocardiografia, diâmetro dos cardiomiócitos e fração volume de colágeno por métodos histológicos. RESULTADOS: Não foram observadas diferenças na PA. O grupo TC apresentou redução da frequência cardíaca de repouso após o período experimental, o que não ocorreu no grupo TA. Foram observadas HC de 38 por cento no grupo SA, 52 por cento no grupo TC e de 64 por cento no grupo TA em relação ao grupo SC. O grupo TA apresentou diminuição da função diastólica em relação aos outros grupos. Os grupos treinados apresentaram aumentos significantes no diâmetro dos cardiomiócitos. Os grupos SA e TA apresentaram aumento na fração volume de colágeno em relação aos grupos SC e TC. CONCLUSÃO: Os resultados apresentados mostram que o treinamento físico de natação induz a HC, principalmente pelo aumento do colágeno intersticial, o que pode levar a prejuízos da função diastólica.

INTRODUCTION: Anabolic-androgen steroids (AAS) associated with physical training induce changes from physiological cardiac hypertrophy (CH) to pathological hypertrophy. However, these studies were performed with strength athletes, and the AAS effects associated with aerobic training are still poorly understood. Thus, the aim of this study was to evaluate the effects of aerobic training and AAS on the cardiac structure and function. METHODS: 28 Wistars rats divided in 4 groups were used: sedentary control (SC), sedentary anabolic (SA), trained control (TC) and trained anabolic (TA). The AAS was administered twice a week (10mg/Kg/week). The swimming training was conducted 5 sessions per week during 10 weeks. We evaluated blood pressure and heart rate by tail plethysmography, ventricular function by echocardiography, cardiomyocyte diameter and collagen volumetric fraction by histological methods. RESULTS: There were no differences in BP. TC group showed reduction in rest heart rate after the experimental period, which did not occur in TA group. CH of 38 percent in SA group; 52 percent in TC group and 64 percent in TA group compared to SC group was observed. TA group presented decrease in diastolic function in relation to other groups. The trained groups showed significant increases in cardiomyocytes diameter. SA and TA groups showed increase in collagen volumetric fraction in relation to SC and TC groups. CONCLUSION: The results show that AAS treatment associated to swimming training induces CH, mainly by the increase in interstitial collagen, which can lead to loss of diastolic function.

Influência dos barorreceptores e da pressão arterial na resposta cardíaca à hipertensão renovascular em ratos / Influence of baroreceptors and of arterial blood pressure in cardiac responses to renovascular hypertension in rats

No presente estudo, duas importantes situações foram abordadas no intuito de se melhor entender os mecanismos homeostáticos dos pressorreceptores na gênese da hipertrofia cardíaca em resposta à hipertensão renovascular: o efeito do tempo de clipe na artéria renal e o efeito dos níveis pressóricos e da variabilidade da pressão arterial. O curso temporal mostrou que, antes mesmo da instalação da hipertensão, há alteração da morfologia cardíaca, qual seja o desenvolvimento de uma hipertrofia ventricular excêntrica e, como forma de mecanismo compensatório, um aumento da expressão de algumas proteínas da homeostase do cálcio (fosfolambam fosforilada pela serina-16 e corrigido pelo fosfolambam total em 100% e fosfolambam fosforilado pela treonina-17 e corrigido pelo fosfolambam total em 54%). Uma vez instalada a hipertensão, observou-se um remodelamento ventricular esquerdo para o tipo concêntrico, com prejuízo da função diastólica e um desbalanço do sistema nervoso autonômico, com aumento da atividade simpática, observado pelo aumento da razão dos componentes de baixa freqüência (LF) e alta freqüência (HF) no tacograma (0,44 ± 0,10 vs. 0,20 ± 0,03 nos controles). A análise do efeito da pressão arterial e da variabilidade da pressão arterial mostrou uma correlação positiva com o grau de hipertrofia ventricular esquerda (r=0,76, p<0,01). A secção cirúrgica dos pressorreceptores somada à implantação do clipe na artéria renal mostrou adaptações cardiovasculares em níveis semelhantes (mesmo nível de hipertensão) e, por vezes maiores (modulação simpática para o coração e para os vasos, hipertrofia ventricular esquerda e disfunção diastólica), ao grupo cuja artéria renal foi estenosada e que permaneceu com os barorreceptores intactos. Estas respostas aconteceram num período de tempo três vezes menor na ausência do barorreflexo. Tais observações ressaltam o importante efeito homeostático do barorreflexo na gênese das respostas cardíacas adaptativas à hipertensão arterial.

In the present study, two important situations were observed to evaluate the role of the baroreceptors in the genesis of cardiac hypertrophy in response to hypertension: the effect of the time-course of the clip in the renal artery and the effect of the level of arterial blood pressure (ABP) and blood pressure variability (ABPV). The time-course evaluation showed that even before hypertension was installed, cardiac alterations could be observed, as a left ventricular eccentric hypertrophy. Compensatory mechanisms, such as an increase in some calcium homeosthatic proteins, could also be noticed (increase in phosphorilated phospholmaban at threonin-17 corrected by total phospholamban in 54% and increase in phosphorilated phospholmaban at serine-16 corrected by total phospholamban in 100%). However, once hypertension was established, left ventricle morphology changed to a concentric hypertrophy, accompanied by a diastolic dysfunction and enhanced sympathetic modulation, observed by relation between low-frequency component (LF) and high-frequency component (HF) at tachogram (0,44 ± 0,10 vs. 0,20 ± 0,03 in control group). ABP and ABPV analyses showed an important positive correlation with the degree of left ventricular hypertrophy (r=0,76, p<0,01). However, the absence of baroreceptors in one of the hypertensive groups, evoked the same cardiovascular alterations (same level of hypertension) or even worse (sympathetic modulation for heart and vessels, left ventricular hypertrophy and diastolic dysfunction) reached by the hypertensive baroreceptors-preserved group. These cardiovascular responses were observed in a period that correspond one third of time to the group with intact baroreflex. These observations lead us to conclude the importance of homeosthatic effects of the baroreflex in the genesis of cardiac responses to hypertension.