Dexamethasone (DEX) treatment often increases blood pressure. Exercise training is an efficient non‐pharmacological intervention to treat hypertension, which is thought to be explained by improved ...microvascular function. Microcirculation related‐microRNAs (miRNAs) play a role in maintaining micro vessel skeletal density. The aim of this study was to investigate if training‐induced miRNAs are associated with exercise training‐dependent prevention of DEX‐induced rarefaction. Wistar rats were trained (treadmill) for 8 weeks or not (sedentary) and then treated with DEX (50 μg/kg per day, s.c.) or saline for 14 days. Carotid artery catheterization for arterial pressure measurements was performed on last day of treatment and tibialis anterior (TA) muscle was collected for morphometric, protein and microRNAs analyses. In sedentary rats, DEX treatment induced hypertension (+27%) concomitantly with capillary density loss (CD, −20.8%) and decreased VEGF (−43.0%), p‐AKT/AKT (−39.6%) and Bcl‐2 (−23.0%) protein levels and increased caspase‐3‐cleaved protein (+34.0%) in TA muscle. In the trained group, however, microRNA‐126 expression was increased (+13.1%), which was followed by enhanced p‐AKT/AKT (+37.7%) and Bcl‐2 (+7.7%), as well as a diminished caspase‐3‐cleaved (−23.1%) protein level. The changes in miRNA‐126 expression were positively correlated with p‐AKT/AKT (r=0.7246) and VEGF (r=0.5224) protein levels. Neither DEX nor training significantly changed miRNA‐16, 21, 221, 222, 155. We concluded that miRNA‐126 upregulation, induced by training, plays an important role in controlling skeletal muscle vessel density. MiRNA126 could be a novel therapeutic agent against DEX‐induced rarefaction.
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Financial support: FAPESP (2018/06998‐7)
This is from the Experimental Biology 2019 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
(1) Background: Arterial stiffness is an important predictor of cardiovascular events. Perindopril and physical exercise are important in controlling hypertension and arterial stiffness, but the ...mechanisms are unclear. (2) Methods: Thirty-two spontaneously hypertensive rats (SHR) were evaluated for eight weeks: SHR
(sedentary); SHR
(sedentary treated with perindopril-3 mg/kg) and SHR
(trained). Pulse wave velocity (PWV) analysis was performed, and the aorta was collected for proteomic analysis. (3) Results: Both treatments determined a similar reduction in PWV (-33% for SHR
and -23% for SHR
) vs. SHR
, as well as in BP. Among the altered proteins, the proteomic analysis identified an upregulation of the EH domain-containing 2 (EHD2) protein in the SHR
group, required for nitric oxide-dependent vessel relaxation. The SHR
group showed downregulation of collagen-1 (COL1). Accordingly, SHR
showed an increase (+69%) in the e-NOS protein level and SHR
showed a lower COL1 protein level (-46%) compared with SHR
. (4) Conclusions: Both perindopril and aerobic training reduced arterial stiffness in SHR; however, the results suggest that the mechanisms can be distinct. While treatment with perindopril increased EHD2, a protein involved in vessel relaxation, aerobic training decreased COL1 protein level, an important protein of the extracellular matrix (ECM) that normally enhances vessel rigidity.
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.
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.
Glucocorticoids have important anti-inflammatory and immunomodulatory activities. Dexamethasone (Dex), a synthetic glucocorticoid, induces insulin resistance, hyperglycemia, and hypertension. The ...hypertensive mechanisms of Dex are not well understood. Previously, we showed that exercise training prior to Dex treatment significantly decreases blood vessel loss and hypertension in rats. In this study, we examined whether the salutary effects of exercise are associated with an enhanced metabolic profile. Analysis of the NAD and ATP content in the tibialis anterior muscle of trained and non-trained animals indicated that exercise increases both NAD and ATP; however, Dex treatment had no effect on any of the experimental groups. Likewise, Dex did not change NAD and ATP in cultured endothelial cells following 24 h and 48 h of incubation with high concentrations. Reduced VEGF-stimulated NO production, however, was verified in endothelial cultured cells. Reduced NO was not associated with changes in survival or the BH4 to BH2 ratio. Moreover, Dex had no effect on bradykinin- or shear-stress-stimulated NO production, indicating that VEGF-stimulated eNOS phosphorylation is a target of Dex's effects. The PTP1B inhibitor increased NO in Dex-treated cells in a dose-dependent fashion, an effect that was replicated by the glucocorticoid receptor inhibitor, RU486. In combination, these results indicate that Dex-induced endothelial dysfunction is mediated by glucocorticoid receptor and PTP1B activation. Moreover, since exercise reduces the expression of PTP1B and normalized insulin resistance in aging rats, our findings indicate that exercise training by reducing PTP1B activity counteracts Dex-induced hypertension in vivo.
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•Dexamethasone (Dex) induces hypertension that is ameliorated by exercise training.•Dex causes skeletal muscle (tibialis anterior) microvascular rarefaction.•Dex does not modify NAD or ATP levels in vivo or in cultured endothelial cells.•Dex alters VEGF but not bradykinin or shear stress-mediated NO activation.•Glucocorticoid receptor or PTPB1 inhibition improves NO signaling in Dex-treatments.
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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)‐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
Dexamethasone (DEX)‐induced hypertension (HT) is associated with autonomic unbalance, increased arterial stiffness, reduced baroreflex gain and cardiac remodeling. Since hypertensive individuals may ...undergo DEX clinical treatment, it is reasonable to think that DEX treatment would exacerbate their arterial pressure, which, in turn, could culminate in a drastic increase on morbi‐mortality risk. Inversely, aerobic (AT) or combined (CT) training have been recommended for HT treatment and we have previously shown the preventive role of exercise training in counteracting DEX‐induced HT. Since nothing is known about the effects of DEX treatment in hypertensive rats, the aim of this study was to investigate if aerobic or combined training, performed before DEX treatment, would modulate autonomic balance, arterial stiffness and cardiac remodeling in spontaneously hypertensive rats (SHR) treated with DEX. Two groups of SHR (200g) underwent aerobic (AT) or combined (CT) training (60% of maximal capacity) for 8 weeks or were kept sedentary and then were treated with DEX (50μg /kg per day, s.c.) or saline (14 days). Wistar rats were used as normotensive control. Transthoracic echocardiogram and pulse wave velocity (PWV) were performed at the end of the protocol. Then, all rats underwent carotid artery catheterization for arterial pressure (AP) measurement and spectral analysis. Left ventricule (LV) was collected, weighed, and used for morphometric analysis. SHR had higher AP, PWV, LV weight, LV mass index (LVMI) and reduced systolic and diastolic function compared with wistar rats. DEX treatment (SD) did not aggravate mean AP (176±11 vs 184±8 mmHg) vs sed SHR (SC), but increased PWV (+17%). In addition, DEX did not alter the ratio between low frequency and high frequency bands of spectral analysis. DEX treatment increased LV diastolic diameter (LVDD/bw,+14%) compared with SC, but significantly decreased isovolumetric relaxation time IVRT (ms, −11%) and collagen density (−21%). Trained groups presented lower values of MAP (−18% and −13%, for AT and CT, respectively, vs SD). PWV was attenuated only by CT (−17%). Autonomic balance was not improved by training in SHR. Improved diastolic function and % of collagen (p<0.06) were observed in TD group only after AT. In conclusion, DEX treatment did not aggravate hypertension and its mechanisms in SHR, which suggests that hypertensive individuals may undergo DEX clinical treatment. Also, exercise training is a good strategy to decrease AP and improve cardiac remodeling in DEX‐treated SHR.
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Funding: FAPESP
This is from the Experimental Biology 2019 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
Sympathetic activity, arteriolar structure, and angiogenesis are important mechanisms modulating hypertension and this study aimed to analyze the effects of perindopril treatment, associated or not ...with exercise training, on the mechanisms that control blood pressure (BP) in hypertensive rats. Spontaneously hypertensive rats (SHR) were allocated into 4 groups: 1/sedentary (S); 2/perindopril (P, 3.0 mg/kg/d); 3/trained (T); and 4/trained + perindopril (TP). Wistar rats were used as normotensive sedentary control group. SHR were assigned to undergo a treadmill training (T) or were kept sedentary. Heart rate, BP, sympathetic activity to the vessels (LF-SBP), and skeletal muscle and myocardial morphometric analyses were performed. BP was significantly lower after all 3 strategies, compared with S and was accompanied by lower LF-SBP (-76%, -53%, and -44%, for P, T, and TP, respectively). Arteriolar vessel wall cross-sectional area was lower after treatments (-56%, -52%, and -56%, for P, T, and TP, respectively), and only TP presented higher arteriolar lumen area. Capillary rarefaction was present in soleus muscle and myocardium in S group and both trained groups presented higher vessel density, although perindopril attenuated this increase in soleus muscle. Although myocyte diameter was not different between groups, myocardial collagen deposition area, higher in S group, was lower after 3 strategies. In conclusion, we may suggest that perindopril could be an option for the hypertensive people who practice exercise and need a specific pharmacological treatment to reach a better BP control, mainly because training-induced angiogenesis is an important response to facilitate blood flow perfusion and oxygen uptake and perindopril did not attenuate this response.
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.
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