Abstract-In this study we investigated the effects of the genetic deletion of the angiotensin (Ang)-(1-7) receptor Mas on heart function. Localization of Mas in the mouse heart was evaluated by binding of rhodamine-labeled Ang-(1-7). Cardiac function was examined using isolated heart preparations. Echocardiography was used to confirm the results obtained with isolated heart studies. To elucidate the possible mechanisms involved in the cardiac phenotype observed in Mas Ϫ/Ϫ mice, whole-cell calcium currents in cardiomyocytes and the expression of collagen types I, III, and VI and fibronectin were analyzed. Ang-(1-7) binding showed that Mas is localized in cardiomyocytes of the mouse heart. Isolated heart techniques revealed that Mas-deficient mice present a lower systolic tension (average: 1.4Ϯ0.09 versus 2.1Ϯ0.03 g in Mas ϩ/ϩ mice), ϮdT/dt, and heart rate. A significantly higher coronary vessel resistance was also observed in Mas-deficient mice. Echocardiography revealed that hearts of Mas-deficient mice showed a significantly decreased fractional shortening, posterior wall thickness in systole and left ventricle end-diastolic dimension, and a higher left ventricle end-systolic dimension. A markedly lower global ventricular function, as defined by a higher myocardial performance index, was observed. A higher delayed time to the peak of calcium current was also observed. The changes in cardiac function could be partially explained by a marked change in collagen expression to a profibrotic profile in Mas-deficient mice. These results indicate that Ang-(1-7)-Mas axis plays a key role in the maintenance of the structure and function of the heart. (Hypertension. 2006;47:996-1002.)

Sleep deprivation is common in Western societies and is associated with increased cardiovascular morbidity and mortality in epidemiological studies. However, the effects of partial sleep deprivation on the cardiovascular system are poorly understood. In the present study, we evaluated 13 healthy male volunteers (age: 31 ± 2 yr) monitoring sleep diary and wrist actigraphy during their daily routine for 12 nights. The subjects were randomized and crossover to 5 nights of control sleep (>7 h) or 5 nights of partial sleep deprivation (<5 h), interposed by 2 nights of unrestricted sleep. At the end of control and partial sleep deprivation periods, heart rate variability (HRV), blood pressure variability (BPV), serum norepinephrine, and venous endothelial function (dorsal hand vein technique) were measured at rest in a supine position. The subjects slept 8.0 ± 0.5 and 4.5 ± 0.3 h during control and partial sleep deprivation periods, respectively (P < 0.01). Compared with control, sleep deprivation caused significant increase in sympathetic activity as evidenced by increase in percent low-frequency (50 ± 15 vs. 59 ± 8) and a decrease in percent high-frequency (50 ± 10 vs. 41 ± 8) components of HRV, increase in low-frequency band of BPV, and increase in serum norepinephrine (119 ± 46 vs. 162 ± 58 ng/ml), as well as a reduction in maximum endothelial dependent venodilatation (100 ± 22 vs. 41 ± 20%; P < 0.05 for all comparisons). In conclusion, 5 nights of partial sleep deprivation is sufficient to cause significant increase in sympathetic activity and venous endothelial dysfunction. These results may help to explain the association between short sleep and increased cardiovascular risk in epidemiological studies.

Several investigators have demonstrated that diabetes is associated with autonomic and myocardial dysfunction. Exercise training is an efficient non-pharmacological treatment for cardiac and metabolic diseases. The aim of the present study was to investigate the effects of exercise training on hemodynamic and autonomic diabetic dysfunction. After 1 week of diabetes induction (streptozotocin, 50 mg/kg, iv), male Wistar rats (222 ± 5 g, N = 18) were submitted to exercise training for 10 weeks on a treadmill. Arterial pressure signals were obtained and processed with a data acquisition system. Autonomic function and intrinsic heart rate were studied by injecting methylatropine and propranolol. Left ventricular function was assessed in hearts perfused in vitro by the Langendorff technique. Diabetes (D) bradycardia and hypotension (D: 279 ± 9 bpm and 91 ± 4 mmHg vs 315 ± 11 bpm and 111 ± 4 mmHg in controls, C) were attenuated by training (TD: 305 ± 7 bpm and 100 ± 4 mmHg). Vagal tonus was decreased in the diabetic groups and sympathetic tonus was similar in all animals. Intrinsic heart rate was lower in D (284 ± 11 bpm) compared to C and TD (390 ± 8 and 342 ± 14 bpm, respectively). Peak systolic pressure developed at different pressures was similar for all groups, but +dP/dt max was decreased and -dP/dt max was increased in D. In conclusion, exercise training reversed hypotension and bradycardia and improved myocardial function in diabetic rats. These changes represent an adaptive response to the demands of training, supporting a positive role of physical activity in the management of diabetes.

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The molecular basis of the beneficial effects associated with exercise training (ET) on overall ventricular function (VF) in heart failure (HF) remains unclear. We investigated potential Ca(2+) handling abnormalities and whether ET would improve VF of mice lacking alpha(2A)- and alpha(2C)-adrenoceptors (alpha(2A)/alpha(2C)ARKO) that have sympathetic hyperactivity-induced HF. A cohort of male wild-type (WT) and congenic alpha(2A)/alpha(2C)ARKO mice in a C57BL/J genetic background (5-7 mo of age) was randomly assigned into untrained and trained groups. VF was assessed by two-dimensional guided M-mode echocardiography. Cardiac myocyte width and ventricular fibrosis were evaluated with a computer-assisted morphometric system. Sarcoplasmic reticulum Ca(2+) ATPase (SERCA2), phospholamban (PLN), phospho-Ser(16)-PLN, phospho-Thr(17)-PLN, phosphatase 1 (PP1), and Na(+)-Ca(2+) exchanger (NCX) were analyzed by Western blotting. ET consisted of 8-wk running sessions of 60 min, 5 days/wk. alpha(2A)/alpha(2C)ARKO mice displayed exercise intolerance, systolic dysfunction, increased cardiac myocyte width, and ventricular fibrosis paralleled by decreased SERCA2 and increased NCX expression levels. ET in alpha(2A)/alpha(2C)ARKO mice improved exercise tolerance and systolic function. ET slightly reduced cardiac myocyte width, but unchanged ventricular fibrosis in alpha(2A)/alpha(2C)ARKO mice. ET significantly increased the expression of SERCA2 (20%) and phospho-Ser(16)-PLN (63%), phospho-Thr(17)-PLN (211%) in alpha(2A)/alpha(2C)ARKO mice. Furthermore, ET restored NCX and PP1 expression in alpha(2A)/alpha(2C)ARKO to untrained WT mice levels. Thus, we provide evidence that Ca(2+) handling is impaired in this HF model and that overall VF improved upon ET, which was associated to changes in the net balance of cardiac Ca(2+) handling proteins.

MiRNAs regulate cardiac development, hypertrophy, and angiogenesis, but their role in cardiac hypertrophy (CH) induced by aerobic training has not previously been studied. Aerobic training promotes physiological CH preserving cardiac function. This study assessed involvement of miRNAs-29 in CH of trained rats. Female Wistar rats (n ϭ 7/group) were randomized into three groups: sedentary (S), training 1 (T1), training 2 (T2). T1: swimming sessions of 60 min/5 days/wk/10 wk. T2: similar to T1 until 8th wk. On the 9th wk rats swam 2ϫ/day, and on the 10th wk 3ϫ/day. MiRNAs analysis was performed by miRNA microarray and confirmed by real-time PCR. We assessed: markers of training, CH by ratio of left ventricle (LV) weight/body wt and cardiomyocytes diameter, pathological markers of CH (ANF, skeletal ␣-actin, ␣/␤-MHC), collagen I and III (COLIAI and COLIIIAI) by real-time PCR, protein collagen by hydroxyproline (OH-proline) concentration, CF and CH by echocardiography. Training improved aerobic capacity and induced CH. MiRNAs-1, 133a, and 133b were downregulated as observed in pathological CH, however, without pathological markers. MiRNA-29c expression increased in T1 (52%) and T2 (123%), correlated with a decrease in COLIAI and COLIIIAI expression in T1 (27%, 38%) and T2 (33%, 48%), respectively. MiRNA-29c was inversely correlated to OH-proline concentration (r ϭ 0.61, P Ͻ 0.05). The E/A ratio increased in T2, indicating improved LV compliance. Thus, these results show that aerobic training increase miR-29 expression and decreased collagen gene expression and concentration in the heart, which is relevant to the improved LV compliance and beneficial cardiac effects, associated with aerobic high performance training. cardiac hypertrophy; collagen; molecular markers; swimming training; physiological cardiac hypertrophy; diastolic function microRNAs (miRNAs) are recognized as a new class of gene expression regulators, consisting of short RNAs, singlestranded, that do not synthesize proteins.MiRNAs are currently potential therapeutic targets and biomarkers in cardiovascular research of various physiological and pathological processes (2,3,(33)(34)(35)(36)(37)40). The action of miRNAs occurs at the posttranscriptional level. MiRNAs negatively regulate the expression of their target genes by coupling to the 3=-untranslated regions (3=-UTR) of mRNA expressed by the target gene (direct modulation) or in the 3=-UTR of mRNA related with the expression of target gene (indirect modulation), which represses its translation into protein (18,19).There are several studies involving miRNAs in pathological cardiac hypertrophy (CH) (2, 3, 29, 35, 36). MiRNAs-1, 133a, and 133b are the best known and highly expressed in heart (36) and already have several targets genes validated, as transcription factors, proteins involved in cellular growth and division, rearrangement of myofibrils and cardiac contractility (34). Carè et al. (2) reported that the decreased expression of miRNA-1 and 133 in vivo and in vitro has a critical role in hypertro...

. Exercise training changes autonomic cardiovascular balance in mice. J Appl Physiol 96: 2174-2178, 2004. First published January 16, 2004 10.1152/ japplphysiol.00870.2003.-Experiments were performed to investigate the influence of exercise training on cardiovascular function in mice. Heart rate, arterial pressure, baroreflex sensitivity, and autonomic control of heart rate were measured in conscious, unrestrained male C57/6J sedentary ( n ϭ 8) and trained mice (n ϭ 8). The exercise training protocol used a treadmill (1 h/day; 5 days/wk for 4 wk). Baroreflex sensitivity was evaluated by the tachycardic and bradycardic responses induced by sodium nitroprusside and phenylephrine, respectively. Autonomic control of heart rate and intrinsic heart rate were determined by use of methylatropine and propranolol. Resting bradycardia was observed in trained mice compared with sedentary animals [485 Ϯ 9 vs. 612 Ϯ 5 beats/min (bpm)], whereas mean arterial pressure was not different between the groups (106 Ϯ 2 vs. 108 Ϯ 3 mmHg). Baroreflex-mediated tachycardia was significantly enhanced in the trained group (6.97 Ϯ 0.97 vs. 1.6 Ϯ 0.21 bpm/ mmHg, trained vs. sedentary), whereas baroreflex-mediated bradycardia was not altered by training. The tachycardia induced by methylatropine was significantly increased in trained animals (139 Ϯ 12 vs. 40 Ϯ 9 bpm, trained vs. sedentary), whereas the propranolol effect was significantly reduced in the trained group (49 Ϯ 11 vs. 97 Ϯ 11 bpm, trained vs. sedentary). Intrinsic heart rate was similar between groups. In conclusion, dynamic exercise training in mice induced a resting bradycardia and an improvement in baroreflex-mediated tachycardia. These changes are likely related to an increased vagal and decreased sympathetic tone, similar to the exercise response observed in humans. bradycardia; autonomic nervous system; baroreflex; blood pressure RESTING BRADYCARDIA, INDUCED by exercise training, has been well documented in humans and animals; however, the mechanisms underlying the effect are not well understood. Studies in humans suggest that increased vagal activity is responsible for the decrease in heart rate (HR) (31, 32). In contrast, in young trained rats the resting bradycardia was more likely due to alterations in cardiac pacemaker function, a regulator of intrinsic heart rate (IHR), rather than to increased vagal activity (24). Moreover, the improvement in baroreflex control of HR observed in trained animals (3, 10, 11) and humans (1, 26) may also play a role in the basal HR changes.Exercise training induces cardiovascular and metabolic changes that are dependent on exercise intensity and duration as well as physiological condition (1, 8-10, 26, 30). Studies in mice demonstrate that treadmill exercise resulted in linear increases in HR, maximum oxygen consumption (V O 2 max ), and respiratory exchange ratio, similar to that seen in larger species (11). A test of ␤-adrenergic stimulation suggested that sympathetic tone was not altered, whereas vagal input was reduced. Swimming (4-w...

Home-based IMT represents an important strategy to improve cardiac and peripheral autonomic controls, functional capacity, and quality of life in patients with CHF.