Purpose
Although the cardioprotective benefits of exercise training are well known, the effects of training on dexamethasone (DEX)-induced arterial stiffness are still unclear. This study was aimed ...at investigating the mechanisms induced by training to prevent DEX-induced arterial stiffness.
Methods
Wistar rats were allocated into 4 groups and submitted to combined training (aerobic and resistance exercises, on alternate days, 60% of maximal capacity, for 74 d) or were kept sedentary: sedentary control rats (SC), DEX-treated sedentary rats (DS), combined training control (CT), and DEX-treated trained rats (DT). During the last 14 d, rats were treated with DEX (50 μg/kg per body weight, per day,
s.c
.) or saline.
Results
DEX increased PWV (+44%
vs
+5% m/s, for DS
vs
SC,
p
<0.001) and increased aortic COL 3 protein level (+75%) in DS. In addition, PWV was correlated with COL3 levels (
r
=0.682,
p
<0.0001). Aortic elastin and COL1 protein levels remained unchanged. On the other hand, the trained and treated groups showed lower PWV values (−27% m/s,
p
<0.001)
vs
DS and lower values of aortic and femoral COL3 compared with DS.
Conclusion
As DEX is widely used in several situations, the clinical relevance of this study is that the maintenance of good physical capacity throughout life can be crucial to alleviate some of its side effects, such as arterial stiffness.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Dexamethasone (DEX)-induced arterial stiffness is an important side-effect, associated with hypertension and future cardiovascular events, which can be counteracted by exercise training. The aim of ...this study was to evaluate the mechanisms induced by combined training to attenuate arterial stiffness and hypertension in spontaneously hypertensive rats treated or not with dexamethasone. Spontaneously hypertensive rats (SHR) underwent combined training for 74 days and were treated with dexamethasone (50 µg/kg
s. c
.) or saline solution during the last 14 days. Wistar rats were used as controls. Echocardiographic parameters, blood pressure (BP) and pulse wave velocity (PWV), as well as histological analyses of the heart and aorta, carotid and femoral arteries were performed. At the beginning, SHR had higher BP and PWV compared with Wistar rats. After 60 days, while BP increased in sedentary SHR, combined exercise training decreased BP and PWV. After 74d, the higher BP and PWV of sedentary SHR was accompanied by autonomic imbalance to the heart, cardiac remodeling, and higher arterial collagen deposition. DEX treatment did not change these parameters. On the other hand, trained SHR had reduced BP and PWV, which was associated with better autonomic balance to the heart, reduced myocardial collagen deposition, as well as lower arterial collagen deposition. The results of this study suggest that combined training, through the reduction of aortic collagen deposition, is an important strategy to reduce arterial stiffness in spontaneously hypertensive rats, and these lower responses were maintained regardless of dexamethasone treatment.
Angiogenesis is an important exercise-induced response to improve blood flow and decrease vascular resistance in spontaneously hypertensive rats (SHR), but some antihypertensive drugs attenuate this ...effect. This study compared the effects of captopril and perindopril on exercise-induced cardiac and skeletal muscle angiogenesis. Forty-eight Wistar rats and 48 SHR underwent 60 days of aerobic training or were kept sedentary. During the last 45 days, rats were treated with captopril, perindopril or water (Control). Blood pressure (BP) measurements were taken and histological samples from the tibialis anterior (TA) and left ventricle (LV) muscles were analyzed for capillary density (CD) and vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2) and endothelial nitric oxide synthase (eNOS) protein level. Exercise increased vessel density in Wistar rats due to higher VEGFR-2 (+17%) and eNOS (+31%) protein level. Captopril and perindopril attenuated exercise-induced angiogenesis in Wistar rats, but the attenuation was small in the perindopril group, and this response was mediated by higher eNOS levels in the Per group compared to the Cap group. Exercise increased myocardial CD in Wistar rats in all groups and treatment did not attenuate it. Both exercise and pharmacological treatment reduced BP of SHR similarly. Rarefaction was found in TA of SHR compared to Wistar, due to lower levels of VEGF (-26%) and eNOS (-27%) and treatment did not avoid this response. Exercise prevented these reductions in control SHR. While rats treated with perindopril showed angiogenesis in the TA muscle after training, those rats treated with captopril showed attenuated angiogenesis (-18%). This response was also mediated by lower eNOS levels in Cap group compared with Per and control group. Myocardial CD was reduced in all sedentary hypertensive compared with Wistar and training restored the number of vessels compared with sedentary SHR. In conclusion, taken into account only the aspect of vessel growth, since both pharmacological treatments reduced BP in SHR, the result of the present study suggests that perindopril could be a drug of choice over captopril for hypertensive practitioners of aerobic physical exercises, especially considering that it does not attenuate angiogenesis induced by aerobic physical training in skeletal and cardiac muscles.
Dexamethasone (DEX)‐induced hypertension is observed in normotensive rats, but little is known about the effects of DEX on spontaneously hypertensive animals (SHR). This study aimed to evaluate the ...effects of DEX on hemodynamics, cardiac hypertrophy and arterial stiffness in normotensive and hypertensive rats. Wistar rats and SHR were treated with DEX (50 μg/kg s.c., 14 d) or saline. Pulse wave velocity (PWV), echocardiographic parameters, blood pressure (BP), autonomic modulation and histological analyses of heart and thoracic aorta were performed. SHR had higher BP compared with Wistar, associated with autonomic unbalance to the heart. Echocardiographic changes in SHR (vs. Wistar) were suggestive of cardiac remodeling: higher relative wall thickness (RWT, +28%) and left ventricle mass index (LVMI, +26%) and lower left ventricle systolic diameter (LVSD, −19%) and LV diastolic diameter (LVDD, −10%), with slightly systolic dysfunction and preserved diastolic dysfunction. Also, SHR had lower myocardial capillary density and similar collagen deposition area. PWV was higher in SHR due to higher aortic collagen deposition. DEX‐treated Wistar rats presented higher BP (~23%) and autonomic unbalance. DEX did not change cardiac structure in Wistar, but PWV (+21%) and aortic collagen deposition area (+21%) were higher compared with control. On the other side, DEX did not change BP or autonomic balance to the heart in SHR, but reduced RWT and LV collagen deposition area (−12% vs. SHRCT). In conclusion, the results suggest a differential effect of dexamethasone on arterial stiffness, myocardial remodeling and blood pressure between normotensive and spontaneously hypertensive rats.
This study aimed to evaluate the effects of DEX on hemodynamics, cardiac hypertrophy, and arterial stiffness in normotensive and spontaneously hypertensive rats (SHR). DEX‐treated Wistar rats presented higher BP accompanied by autonomic unbalance to the heart and aortic stiffness. On the other side, hypertension, autonomic unbalance to the heart and arterial stiffness were maintained in SHR after DEX treatment, suggesting a differential effect of DEX between normotensive and hypertensive rats.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Since cardiac inflammation has been considered an important mechanism involved in heart failure, an anti-inflammatory treatment could control cardiac inflammation and mitigate the worsening of ...cardiac remodeling. This study evaluated the effects of dexamethasone (DEX) and ramipril treatment on inflammation and cardiac fibrosis in an experimental model of heart failure induced by supravalvular aortic stenosis. Wistar rats (21d) were submitted to an aortic stenosis (AS) protocol. After 21 weeks, an echocardiogram and a maximal exercise test were performed, and after 24 weeks, rats were treated with DEX, ramipril or saline for 14d. The left ventricle (LV) was removed for histological and inflammatory marker analyses. The AS group showed exercise intolerance (-32% vs. Sham), higher relative wall thickness (+63%), collagen deposition and capillary rarefaction, followed by cardiac disfunction. Both treatments were effective in reducing cardiac inflammation, but only DEX attenuated the increased relative wall thickness (-17%) and only ramipril reduced LV fibrosis. In conclusion, both DEX and ramipril decreased cardiac inflammatory markers, which probably contributed to the reduced cardiac fibrosis and relative wall thickness; however, treated AS rats did not show any improvement in cardiac function. Despite the complex pharmacological treatment of heart failure, treatment with an anti-inflammatory could delay the patient's poor prognosis.
Microcirculation maintenance is associated with microRNAs. Nevertheless, the role of microRNAs induced by training in preventing dexamethasone (DEX)-induced microvascular rarefaction remains unknown. ...The study aim was to investigate if training-induced microRNAs are able to improve microcirculation proteins and prevent DEX-induced microvascular rarefaction. Rats underwent training for 8 weeks and then were treated with DEX (50 μg/kg per day, s.c.) for 14 days. Arterial pressure was measured and tibialis anterior (TA) muscle was collected for analyses. DEX induced hypertension concomitantly with capillary density loss (CD, −23.9%) and decrease of VEGF (−43.0%), p-AKT/AKT (−39.6%) and Bcl-2 (−23.0%) and an increase in caspase-3-cleaved protein level (+34.0%) in TA muscle. Training upregulated microRNA-126 expression (+13.1%), prevented VEGF (+61.4%), p-AKT/AKT (+37.7%), Bcl-2 (+7.7%) decrease and caspase-3-cleaved (−23.1%) increase associated with CD (+54.7%) reduction and hypertension prevention. MiRNA-126 upregulation, induced by training, plays a role in controlling microcirculation, which may be a potential target against DEX-induced microvascular rarefaction.
•Dexamethasone induces microvessel loss in skeletal muscle.•Exercise training prevents dexamethasone-induced rarefaction.•Anti-apoptotic, apoptotic and angiogenic proteins are associated with vessels density.•Exercise training induces microRNA-126 upregulation.•miRNA-126 upregulation induced by exercise training is associated with rarefaction prevention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Dexamethasone (DEX) has important anti-inflammatory activities; however, it induces hypertension and skeletal muscle microcirculation rarefaction. Nevertheless, nothing is known about DEX outcomes on ...cardiac microcirculation. By contrast, exercise training prevents skeletal and cardiac microvessel loss because of microRNA expression and a better balance between their related angiogenic and apoptotic proteins in spontaneously hypertensive rats. The purpose of this study was to investigate whether DEX and/or exercise training could induce microRNA alterations leading to cardiac angiogenesis or microvascular rarefaction. Animals performed 8 weeks of exercise training and were treated with DEX (50 μg/kg per day, subcutaneously) for 14 days. Cardiovascular parameters were measured, and the left ventricle muscle was collected for analyses. DEX treatment increased arterial pressure and did not cause cardiac microcirculation rarefaction. Treadmill training prevented the DEX-induced increase in arterial pressure. In addition, training, regardless of DEX treatment, increased microRNA-126 expression, phospho-protein kinase B/protein kinase B, and endothelial nitric oxide synthase levels associated with cardiac angiogenesis. In conclusion, this study suggests, for the first time, that treadmill training induces myocardial angiogenesis because of angiogenic pathway improvement associated with an increase in microRNA-126. Furthermore, DEX, per se, did not cause capillary density alterations and did not attenuate cardiac angiogenesis induced by training.
Introduction:
Dexamethasone (DEX)-induced hypertension and cardiac remodeling are still unclear, especially in spontaneously hypertensive rats (SHR). On the other side, exercise training is a good ...strategy to control hypertension. Therefore, this study investigated the effects of DEX treatment and physical training on arterial pressure and cardiac remodeling in SHR.
Material and Methods:
SHR underwent treadmill training (5 days/week, 1h/session, at 50-60% of maximal capacity, 0% degree, 75 days) and received low-dose of DEX (50µg/kg, s.c.) during the last 15 days. Sedentary Wistar rats (W) were used as control. Echocardiography and artery catheterization were performed for cardiac remodeling and function, arterial pressure and autonomic nervous system analyses. In addition, left ventricle (LV) capillary density, myocyte diameter and collagen deposition area were analyzed using specific histological staining.
Results:
Low-dose of DEX treatment did not exacerbate arterial pressure of SHR and trained groups had lower values, regardless of DEX. DEX and training decreased relative left ventricle wall thickness (RWT) and determined LV angiogenesis (+19%) and lower collagen deposition area (−22%). In addition, it determined increased left ventricular diastolic diameter. These changes were followed by improvements on systolic and diastolic function, since it was observed increased posterior wall shortening velocity (PWSV) and reduced isovolumetric relaxation time (IVRT).
Conclusion:
In conclusion, this study is unique to indicate that low-dose of DEX treatment does not exacerbate arterial pressure in SHR and, when associated with training, it improves LV systolic and diastolic function, which may be due to LV angiogenesis and reduction of wall collagen deposition area.
It has been shown that chronic treatment with dexamethasone (DEX) increase blood pressure (BP) in normotensive rats, however, nothing is known about the effects of DEX treatment in spontaneously ...hypertensive rats (SHR). On the other hand, exercise training (T) has been recommended as a non‐pharmacological treatment for hypertension. Thus, the aim of this study was to investigate the preventive role of T in counteracting DEX‐induced BP increase in normotensive and SHR. Rats were randomly allocated into 8 groups: Wistar sedentary control (WSC), Wistar sedentary treated with DEX (WSD), Wistar trained control (WTC), Wistar trained and treated with DEX (WTD), SHR sedentary control (SHRSC), SHR sedentary treated with DEX (SHRSD), SHR trained control (SHRTC) and SHR trained and treated with DEX (SHRTD). All groups underwent T protocol (treadmill, 60% of physical capacity, 5 days/week, 8 weeks) or were kept sedentary. Then, rats were treated with DEX or saline (0.05 mg/kg per day, s.c., 14 days). Systolic arterial pressure (SAP) was measured by carotid artery catheterization and cardiovascular autonomic modulation to the heart was evaluated by spectral analysis. In addition, tibialis anterior (TA) muscle was collected for morphometric analysis. In Wistar rats, DEX treatment increased SAP (130 ± 5 vs 106 ± 6 mmHg, for SD vs SC, respectively) associated with an increase in low‐frequency spectral power (LF) (45.1 ± 5.9 vs 18.7 ± 4.8 nu, for SD vs SC, respectively) and a decrease in high‐frequency (HF) spectral power (54.8 ± 5.9 vs 81.2 ± 4.8 nu, for SD vs SC, respectively) of pulse interval; also DEX decreased capillary‐to‐fiber ratio (C:F ratio) (0.7 ± 0.02 vs 0.9 ± 0.01, for SD vs SC, respectively) in TA muscle, without affecting wall‐to‐lumen ratio (W/L ratio). Although SHR presented higher SAP (149 ± 7 vs 106 ± 6 mmHg, for SHRSC vs WSC, respectively) and W/L ratio (0.91 ± 0.09 vs 0.58 ± 0.08, for SHRSC vs WSC, respectively) as well as lower values of C:F ratio (0.7 ± 0.04 vs 0.9 ± 0.01, for SHRSC vs WSC, respectively), compared with Wistar rats, DEX treatment did not produce any further alterations in these parameters. On the other hand, T, in Wistar rats, was able to attenuate SAP increase (122 ± 4 vs 130 ± 5 mmHg, for TD vs SD, respectively), LF increase (27.6 ± 6.2 vs 45.1 ± 5.9 nu, for TD vs SD, respectively), HF decrease (72.3 ± 6.2 vs 54.8 ± 5.9 nu, for TD vs SD, respectively) of pulse interval and also C:F ratio decrease (1.0 ± 0.02 vs 0.7 ± 0.02, for TD vs SD, respectively) in TA muscle. In addition, in SHR, T was effective to reduce SAP (121 ± 5 vs 151 ± 8 mmHg, for TD vs SD, respectively), to increase C:F ratio (1.0 ± 0.04 vs 0.7 ± 0.02, for TD vs SD, respectively) and to decrease arterioles W/L ratio (0.58 ± 0.09 vs 0.91 ± 0.08, for TD vs SD, respectively) in TA muscle. In conclusion, these results allow us to suggest that T was able to attenuate DEX‐induced BP increase in Wistar rats, associated with an improvement of cardiovascular autonomic modulation and skeletal muscle microcirculation. In addition, T was able to decrease BP in SHR, mainly through decreases in arterioles W/L ratio and improvements in microcirculation, independent of DEX treatment.
Support or Funding Information
São Paulo Research Foundation
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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