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BACKGROUND: The purpose of this study was to investigate whether or not angiotensin II type 1 receptor blocker irbesartan (ARB) with a partial agonist of PPAR-γ could protect against chronic nocturnal intermittent hypoxia (CIH)-induced cardiac Fas/FasL-mediated to mitochondria-mediated apoptosis. METHODS: Sprague-Dawley rats were in a normoxic control group (CON-G), or rats were in a chronic nocturnal intermittent hypoxia group (HP-G, from 3 to 7% oxygen versus 21% oxygen per forty seconds cycle, nocturnally 8 h per day for 1 month), or rats were in a chronic nocturnal intermittent hypoxia group pretreated with ARB (50 mg/kg/day, S.C.) (ARB-HP-G). Echocardiography, H&E staining, TUNEL staining, and Western blotting were measured in the left ventricle. RESULTS: Hypoxia-induced SIRT1 degradation, Fas receptors, FADD, active caspase-8 and caspase-3 (Fas/FasL apoptotic pathway) and Bax, tBid, active caspase-9 and -3 (mitochondrial apoptotic pathway) and TUNEL-positive apoptosis were reduced in ARB-HP-G when compared with HP-G. IGF-I, IGF1 receptor, p-PI3k, p-Akt, Bcl2, and Bcl-XL (IGF1/PI3K/AKT pro-survival pathway) were increased in ARB-HP-G compared to HP-G. CONCLUSIONS: Our findings suggest that the ARB may prevent cardiac Fas/FasL to mitochondrial apoptotic pathways and enhance cardiac IGF1/PI3K/AKT pro-survival pathway in the sleep apnea model associated with JNK de-activation and SIRT1 upregulation. ARB prevents chronic sleep apnea-enhanced cardiac apoptosis via enhancing survival pathways.
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Sirtuina 1 , Síndromes de la Apnea del Sueño , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , Animales , Apoptosis , Hipoxia , Irbesartán , Miocardio , Oxígeno , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Ratas , Ratas Sprague-Dawley , Regulación hacia ArribaRESUMEN
Exercise training is often considered the cornerstone of nonpharmacological therapy for postmenopausal hypertension while aerobic exercise is the mainstay of life style modification for antihypertension. Moderate-intensity aerobic exercise is well tolerated on most days of the week by most people with postmenopausal hypertension and is not suspected to detract from exercise adherence. That being said, moderate aerobic exercise may be superior for eliciting cardiovascular benefits in hypertensive postmenopausal women and resistance exercise may offer desirable benefits. The beneficial outcomes of exercise training for hypertensive postmenopausal women include improvements in blood pressure, autonomic tone, baroreflex sensitivity, oxidative stress, nitric oxide (NO), bioavailability, and lipid profiles, as well as cardiovascular function and cardiorespiratory fitness. This partly explains the fact that exercise training programs have a positive effect for cardiovascular disease in hypertensive postmenopausal women. This review is to collect and present the literature of exercise training in postmenopausal hypertension. Our review may provide the current understanding of beneficial effects and mechanisms of exercise intervention for prevention and treatment of stage 1 to 2 hypertensive postmenopausal women.
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Fenómenos Fisiológicos Cardiovasculares , Ejercicio Físico , Hipertensión/etiología , Hipertensión/fisiopatología , Posmenopausia , Entrenamiento de Fuerza , Animales , Antioxidantes/metabolismo , Apoptosis , Presión Sanguínea , Índice de Masa Corporal , Femenino , Frecuencia Cardíaca , Humanos , Hipertensión/metabolismo , Hipertensión/patología , Metabolismo de los Lípidos , Óxido Nítrico , Estrés Oxidativo , Remodelación VentricularRESUMEN
The purpose of this study was to evaluate the effects of exercise training on renal fibrosis in hypertensive rats. Masson's trichrome staining and Western blotting were performed on the excised renal cortex from sixteen male spontaneously hypertensive rats (SHR), which were randomly divided into either a sedentary hypertensive group (SHR) or exercise hypertensive group (SHR-EX, running on an exercise treadmill for 60 min/day, 5 sessions/week, for 12 weeks), and from eight male Wistar-Kyoto rats which served as a sedentary normotensive group (WKY). The systolic blood pressure (SBP) and renal fibrosis in hypertensive rats improved after exercise training. The inflammatory-related protein levels of interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), as well as the fibrotic-related protein levels of transforming growth factor-beta (TGF-ß), phospho-Smad2/3 (p-Smad2/3), connective tissue growth factor (CTGF), matrix metalloproteinase-9 (MMP-9), and matrix metalloproteinase-2 (MMP-2) were decreased in the SHR-EX group when compared with the SHR group. Exercise training suppressed the hypertension-induced renal cortical inflammatory and fibrotic pathways in hypertensive rat models. These findings might indicate a new therapeutic effect for exercise training to prevent renal fibrosis in hypertensive nephropathy.
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Terapia por Ejercicio , Fibrosis/terapia , Hipertensión/terapia , Enfermedades Renales/terapia , Animales , Factor de Crecimiento del Tejido Conjuntivo/genética , Ciclooxigenasa 2/genética , Fibrosis/genética , Fibrosis/fisiopatología , Regulación de la Expresión Génica/genética , Humanos , Hipertensión/genética , Hipertensión/fisiopatología , Interleucina-6/genética , Enfermedades Renales/genética , Enfermedades Renales/fisiopatología , Metaloproteinasa 9 de la Matriz/genética , Ratas , Ratas Endogámicas SHR/genética , Ratas Endogámicas SHR/fisiología , Conducta Sedentaria , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Postmenopause is associated with the development of cardiovascular disease, such as hypertension. However, limited information is available regarding effects of exercise on cardiovascular responses and its underlying mechanisms in the simultaneous postmenopausal and hypertensive status. We aimed to investigate whether acute exercise could enhance vasodilation mediated by acetylcholine (ACh) and sodium nitroprusside (SNP) in ovariectomized hypertensive rats. The fifteen-week-old female spontaneously hypertensive rats (SHR) were bilaterally ovariectomized, at the age of twenty-four weeks, and randomly divided into sedentary (SHR-O) and acute exercise (SHR-OE) groups. Age-matched WKY rats were used as the normotensive control group. The SHR-OE group ran on a motor-driven treadmill at a speed of 24 m/min for one hour in a moderate-intensity program. Following a single bout of exercise, rat aortas were isolated for the evaluation of the endothelium-dependent (ACh-induced) and endothelium-independent (SNP-induced) vasodilation by the organ bath system. Also, the serum levels of oxidative stress and antioxidant activities, including malondialdehyde (MDA), superoxide dismutase (SOD), and catalase, were measured after acute exercise among the three groups. We found that acute exercise significantly enhanced the ACh-induced vasodilation, but not the SNP-induced vasodilation, in ovariectomized hypertensive rats. This increased vasodilation was eliminated after the inhibition of nitric oxide synthase (NOS). Also, the activities of SOD and catalase were significantly increased after acute exercise, whereas the level of MDA was comparable among the three groups. These results indicated that acute exercise improved the endothelium-dependent vasodilating response to ACh through the NOS-related pathway in ovariectomized hypertensive rats, which might be associated with increased serum antioxidant activities.
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Acetilcolina/farmacología , Hipertensión/fisiopatología , Ovariectomía , Condicionamiento Físico Animal , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Antioxidantes/metabolismo , Presión Sanguínea/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Frecuencia Cardíaca/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Conducta SedentariaRESUMEN
To investigate whether the coexistence of hypertension and ovariectomy will increase cardiac Fas receptor and mitochondrial-dependent apoptotic pathways, histopathological analysis, the TUNEL assay and Western blotting were performed on the excised hearts from three groups of female spontaneously hypertensive rats (SHR), which were divided into a sham-operated group (SHR-Sham), bilaterally ovariectomized group (SHR-OVX) and normotensive Wistar Kyoto rats (WKY). Compared with the WKY group, the SHR-Sham group exhibited decreased protein levels of ERα, ERß, p-Akt/Akt, Bcl-2, Bcl-xL and p-Bad and decreased further in the SHR-OVX group, as well as protein levels of t-Bid, Bak, Bad, Bax, cytochrome c, activated caspase-9 and activated caspase-3 (mitochondria-dependent apoptosis) increased in the SHR-Sham group and increased further in the SHR-OVX group. Compared with the WKY group, protein levels of Fas ligand, TNF-α, Fas death receptors, TNFR1, FADD and activated caspase-8 (Fas receptor-dependent apoptosis) increased in the SHR-Sham group, but did not increase in the SHR-OVX group, except Fas ligand and TNF-α. The coexistence of hypertension and ovariectomy attenuated the estrogen receptor survival pathway and appeared to additively increase the cardiac mitochondria-dependent, but not the Fas receptor-dependent apoptosis pathway, which might provide one possible mechanism for the development of cardiac abnormalities in hypertensive postmenopausal women.
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Apoptosis/fisiología , Hipertensión/complicaciones , Miocardio/patología , Ovariectomía/efectos adversos , Animales , Presión Sanguínea/fisiología , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Femenino , Miocardio/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo , Receptor fas/metabolismoRESUMEN
To determine the effects of mat Pilates training on blood pressure, inflammatory, and antioxidative markers in hypertensive elderly people, 34 hypertensive subjects aged 60-75 years were randomly divided into a control group (CON; n = 17) and a mat Pilates training group (MP; n = 17). The CON participants conducted normal daily activities and participated in neither organized exercises nor sports training, while those in the MP group received mat Pilates training for 60 min three times/week for 12 weeks. Parameters including blood pressure, cardiovascular function, nitric oxide (NO), tumor necrotic factor-alpha (TNF-α), superoxide dismutase (SOD), and malonaldehyde (MDA) were collected at baseline and the end of 12 weeks. The MP group had significantly decreased blood pressure, improved cardiovascular variables, decreased MDA and TNF-α, and increased NO and SOD compared with the CON group and the pre-training period (p < 0.05). In conclusion, these findings demonstrate the positive effects of 12 weeks of mat Pilates training in terms of reducing blood pressure and increasing blood flow related to improvements in anti-inflammatory and antioxidative markers in hypertensive elderly people. Mat Pilates training might be integrated as an alternative therapeutic exercise modality in clinical practice for hypertensive elderly individuals.
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The effects of low-level laser therapy (LLLT) on tumor growth are inconsistent. In this study, we investigated the effects of LLLT on melanoma tumor growth and angiogenesis. C57/BL6 mice were challenged with B16F10 melanoma cells and treated with LLLT for 5 consecutive days; untreated mice were used as controls. Tumor weight, angiogenesis, immunohistochemistry, and protein levels were compared between the treated and untreated mice. In an in vitro experiment, B16F10 cells were treated with LLLT. Proteins were extracted and subjected to Western blot analysis for analyzing signaling pathways. Compared with the findings in the untreated mice, tumor weight substantially increased in the treated mice. Both immunohistochemical and Western blot analyses revealed markedly increased levels of CD31, a biomarker of vascular differentiation, in the LLLT group. In B16F10 cells, LLLT considerably induced the phosphorylation of extracellular signal-regulated kinase (ERK), which, in turn, phosphorylated p38 mitogen-activated protein kinase (MAPK). Furthermore, LLLT induced the expression of vascular endothelial growth factor, but not hypoxia-inducible factor-1α, through the ERK/p38 MAKP signaling pathways. Our findings indicate that LLLT induces melanoma tumor growth by promoting angiogenesis. Therefore, it should be avoided in patients with melanoma.
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Arterial stiffness is a reliable independent predictor of cardiovascular events. Exercise training might enhance arterial compliance through improved metabolic health status. Different modes of exercise may have different effects on arterial stiffness. However, the interactions among different modes of exercise on endothelial senescence, the development of arterial vascular stiffness, and the associated molecular mechanisms are not completely understood. In this narrative review, we evaluate the current evidence focusing on the effects of various exercise modes on arterial stiffness and vascular health, and the known underlying physiological mechanisms are discussed as well. Here, we discuss the most recent evidence of aerobic exercise, high-intensity interval training (HIIT), and resistance exercise (RE) on arterial stiffness and endothelial senescence in physiological and cellular studies. Indeed, aerobic, HIIT, and progression RE-induced arterial compliance may reduce arterial stiffness by effectively promoting nitric oxide (NO) bioavailability and reducing endothelial senescence. However, the transient increase in inflammation and sympathetic activation may contribute to the temporary elevation in arterial stiffness following whole-body high-intensity acute resistance exercise.
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Rigidez Vascular , Ejercicio Físico , Arterias , Estado de Salud , Senescencia CelularRESUMEN
This study aimed to conduct a meta-analysis of randomized controlled trials to examine the effects of the short-foot exercise (SFE) compared to foot orthosis or other types of interventions. Eligibility criteria involved participants with flatfoot engaging in the SFE compared to other forms of intervention or control groups without specific intervention. Relevant studies published before the end of June 2022 were identified from databases. A meta-analysis was performed by calculating the mean differences (MD) and standard MD (SMD) using the random effects model. Six trials with 201 patients (out of 609 records) that met selection criteria were reviewed. Five of the six trials implemented distinct interventions in the control group such as shoe insoles and muscle strengthening exercises, while in the remaining trial, controls received no intervention. The SFE group significantly reduced the navicular drop test (NDT) values (MD: -0.23; 95% confidence interval: -0.45 to -0.02; p = 0.04) and the foot posture index (FPI-6) score (MD: -0.67; 95% confidence interval: -0.98 to -0.36; p < 0.0001) when compared to the control group. The muscle hypertrophy did not differ significantly between the groups. The SFE may contribute more benefits than other intervention as it affects flatfoot individuals' foot alignment. Hence, the SFE is recommended as a beneficial dynamic support when facing flatfoot problems.
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Pie Plano , Terapia por Ejercicio , Pie Plano/terapia , Pie/fisiología , Humanos , Hipertrofia , MúsculosRESUMEN
BACKGROUND: The present study investigated whether angiotensin II type 1 receptor blocker irbesartan (ARB) and partial agonist of PPAR-γ prevents heart apoptosis by suppressing cardiac Fas/FasL-mediated to mitochondria-mediated apoptosis in the hearts of hypertensive rat model. METHODS: Cardiac function using echocardiography, H&E staining, TUNEL assay, and Western blotting were measured in the excised hearts from three groups, i.e., an untreated hypertensive group (SHR), an ARB-treated hypertensive group (50 mg/kg/day, S.C., SHR-ARB), and untreated normotensive Wistar-Kyoto rats (WKY). RESULTS: Fas Ligand, Fas death receptors, FADD, active caspase-8, active caspase-3 (Fas/FasL-mediated apoptotic pathway), as well as Bax, cytochrome c, active caspase-9 and -3 (mitochondria-mediated apoptotic pathway), IGF-II, and p-JNK were decreased in SHR-ARB group when compared with the SHR group. SIRT1, PGC-1α, Bcl2, and Bcl-xL (SIRT1/PGC-1α pro-survival pathway) were increased in the SHR-ARB group when compared with the SHR group. CONCLUSIONS: Our findings suggested that the ARB might prevent cardiac Fas/FasL-mediated to mitochondria-mediated apoptosis pathway in the hypertensive model associated with IGF-II, p-JNK deactivation, and SIRT1/PGC-1α pro-survival pathway upregulation. ARB prevents hypertension-enhanced cardiac apoptosis via enhancing SIRT1 longevity signaling and enhances the mitochondrial biogenetic survival pathway.
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The physiological changes associated with aging deleteriously impact cardiovascular function and regulation and therefore increase the risk of developing cardiovascular disease. There is substantial evidence that changes in the autonomic nervous system and arterial stiffness play an important role in the development of cardiovascular disease during the aging process. Exercise is known to be effective in improving autonomic regulation and arterial vascular compliance, but differences in the type and intensity of exercise can have varying degrees of impact on vascular regulatory responses and autonomic function. There is still little evidence on whether there are differences in the response of exercise interventions to cardiovascular modulatory effects across the lifespan. In addition, acute interval exercise challenges can improve autonomic modulation, although the results of interval exercise on autonomic physiological parameters vary. Therefore, this narrative review focuses on evaluating the effects of acute interval exercise on blood pressure regulation and autonomic responses and also incorporates studies investigating different age groups to evaluate the effects of acute interval exercise on the autonomic nervous system. Herein we also summarize existing literature examining the acute cardiovascular responses to varied modes of interval exercise, as well as to further compare the benefits of interval exercise with other types of exercise on autonomic regulation and arterial stiffness. After reviewing the existing literature, it has been shown that with advancing age, changes in the autonomic nervous activity of interval exercise result in significant impacts on the cardiovascular system. We document that with advancing age, changes in the autonomic nerves lead to aging of the nervous system, thereby affecting the regulation of blood pressure. According to the limited literature, interval exercise is more effective in attenuating arterial stiffness than continuous exercise, but the difference in exercise benefits may depend on the training mode, intensity, duration of exercise, and the age of participants. Therefore, the benefits of interval exercise on autonomic and arterial stiffness improvement still warrant investigation, particularly the impact of age, in future research.
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BACKGROUND: An inappropriate accumulation of fibrillar collagen is a common pathologic feature of early aged hypertensive heart disease, but little information regarding the effects of exercise training on cardiac fibrosis in hypertension is available. The purpose of this study was to evaluate the effects of exercise training on cardiac fibrotic pathways in early aged hypertensive rats. METHODS: Masson's trichrome staining and Western blotting were performed on the excised left ventricle from twenty male spontaneously hypertensive rats at age of 48 weeks, which were randomly divided into either a sedentary hypertensive group (SHR) or exercise hypertensive group (SHR-EX, running on a treadmill running occurred 5 days/week for 60 min/day, for 12 weeks), and from age-matched male Wistar-Kyoto normotensive controls (WKY). RESULTS: Interstitial fibrosis was reduced in the SHR-Ex group when compared with the SHR group. The fibrotic-related protein levels of AT1R, FGF23, LOX-2, TGF-ß, CTGF, p-Smad 2/3, MMP-2/TIMP-2, MMP-9/TIMP-1, uPA and collagen I were decreased in the SHR-EX group, when compared with the SHR group. CONCLUSIONS: Exercise training suppresses early aged hypertensive heart-induced LOX-2/TGF-ß-mediated fibrotic pathways associated with decreasing AT1R and FGF23, which might provide a new therapeutic effect for exercise training to prevent adverse cardiac fibrosis and myocardial abnormalities in early aged hypertension.
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Cardiopatías , Hipertensión , Animales , Terapia por Ejercicio , Fibrosis , Cardiopatías/etiología , Cardiopatías/prevención & control , Hipertensión/complicaciones , Masculino , Miocardio/patología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: Adjuvant chemotherapies are commonly used for treating early-stage breast cancer. However, whether chemotherapeutic regimens affect exercise tolerance and cardiovascular responses remains unclear. Therefore, we investigated the effects of receiving CAF and AC-T on exercise tolerance and cardiovascular responses in patients with early-stage breast cancer. METHODS: Thirty-four patients with breast cancer (age: 44 ± 1 years; stage I-II) received either CAF (n = 15) or AC-T (n = 19), depending on clinical decisions. Their step-exercise tolerance and cardiovascular responses were assessed before and after chemotherapy. RESULTS: After chemotherapy, there were no differences in baseline measurements between patients receiving CAF or AC-T. The increases in resting heart rate (RHR) of those receiving AC-T was significantly greater than that of those receiving CAF. CAF and AC-T did not result in increased pulse wave velocity (PWV), yet the subendocardial viability ratio (SEVR) in patients receiving AC-T was significantly lower than the baseline. Greater change in post-exercise heart rate recovery (recovery HR) after chemotherapy was observed in those who had received AC-T; the Recovery HR in AC-T patients was significantly higher during post-exercise period than that in CAF patients. CONCLUSIONS: AC-T chemotherapy increases RHR and impairs exercise tolerance after chemotherapy more than CAF. Moreover, AC-T also lowers myocardial perfusion more than CAF after chemotherapy.
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This study aimed to investigate the aging-related endothelial dysfunction mediated by insulin and insulin-like growth factor-1 (IGF-1) and antioxidant deficiency in hypertension. Male spontaneously hypertensive rats (SHRs) and age-matched normotensive Wistar-Kyoto rats (WKYs) were randomly divided into 24-week-old (younger) and 48-week-old (older) groups, respectively. The endothelial function was evaluated by the insulin- and IGF-1-mediated vasorelaxation of aortic rings via the organ bath system. Serum levels of nitric oxide (NO), malondialdehyde (MDA), catalase, and total antioxidant capacity (TAC) were examined. The insulin- and IGF-1-mediated vasorelaxation was significantly impaired in both 24- and 48-week-old SHRs compared with age-matched WKYs and was significantly worse in the 48-week-old SHR than the 24-week-old SHR. After pretreatments of phosphoinositide 3-kinase (PI3K) or NO synthase (NOS) inhibitors, the insulin- and IGF-1-mediated vasorelaxation became similar among four groups. The serum level of MDA was significantly increased, while the NO, catalase, and TAC were significantly reduced in the 48-week-old SHR compared with the 24-week-old SHR. This study demonstrated that the process of aging additively affected insulin- and IGF-1-mediated endothelial dysfunction in SHRs, which could be partly attributed to the reduced NO production and antioxidant deficiency.
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This study aimed to investigate cerebral cortex apoptosis on the early aged hypertension and the effects of green tea flavonoid epigallocatechin-3-gallate (EGCG). Twenty-four rats were divided into three groups: a control Wistar-Kyoto group (WKY, n = 8), a spontaneously early aged hypertensive group (SHR, n = 8), and an early aged hypertension with EGCG treatment group (SHR-EGCG, n = 8; daily oral EGCG 200 mg/kg-94%, 12 weeks). At 48 weeks old, blood pressures (BPs) were evaluated and cerebral cortexes were isolated for TUNEL assay and Western blotting. Systolic, diastolic, and mean blood pressure levels in the SHR-EGCG were reduced compared to the SHR. The percentage of neural cell deaths, the levels of cytosolic Endonuclease G, cytosolic AIF (Caspase-independent apoptotic pathway), Fas, Fas Ligand, FADD, Caspase-8 (Fas-mediated apoptotic pathway), t-Bid, Bax/Bcl-2, Bak/Bcl-xL, cytosolic Cytochrome C, Apaf-1, Caspase-9 (Mitochondrial-mediated apoptotic pathway), and Caspase-3 (Fas-mediated and Mitochondria-mediated apoptotic pathways) were increased in the SHR relative to WKY and reduced in SHR-EGCG relative to SHR. In contrast, the levels of Bcl-2, Bcl-xL, p-Bad, 14-3-3, Bcl-2/Bax, Bcl-xL/Bak, and p-Bad/Bad (Bcl-2 family-related pro-survival pathway), as well as Sirt1, p-PI3K/PI3K and p-AKT/AKT (Sirt1/PI3K/AKT-related pro-survival pathway), were reduced in SHR relative WKY and enhanced in SHR-EGCG relative to SHR. In conclusion, green tea flavonoid epigallocatechin-3-gallate (EGCG) might prevent neural apoptotic pathways and activate neural survival pathways, providing therapeutic effects on early aged hypertension-induced neural apoptosis.
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The purpose of this study was to evaluate the effects of diosgenin on the D-galactose-induced cerebral cortical widely dispersed apoptosis. Male 12-week-old Wistar rats were divided into four groups: Control (1mg/kg/day of saline, i.p.), DD0 (150mg/kg/day of D-galactose, i.p.), DD10, and DD50 (D-galactose+10 or 50mg/kg/day of diosgenin orally). After eight weeks, histopathological analysis, positive TUNEL and Western blotting assays were performed on the excised cerebral cortex from all four groups. The TUNEL-positive apoptotic cells, the components of Fas pathway (Fas, FADD, active caspase-8 and active caspase-3), and mitochondria pathway (t-Bid, Bax, cytochrome c, active caspase-9 and active caspase-3) were increased in the DD0 group compared with the control group, whereas they were decreased in the DD50 group. The components of survival pathway (p-Bad, Bcl-2, Bcl-xL, IGF-1, p-PI3K and p-AKT) were increased in the DD50 group compared to the control group, whereas the levels of Bcl-xL, p-PI3K, and p-AKT were also compensatorily increased in the DD0 group compared to the control group. Taken together, diosgenin suppressed D-galactose-induced neuronal Fas-dependent and mitochondria-dependent apoptotic pathways and enhanced the Bcl-2 family associated pro-survival and IGF-1-PI3K-AKT survival pathways, which might provide neuroprotective effects of diosgenin for prevention of the D-galactose-induced aging brain.
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Envejecimiento , Apoptosis/efectos de los fármacos , Diosgenina/farmacología , Fármacos Neuroprotectores , Animales , Encéfalo/metabolismo , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Mitocondrias/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Receptor fas/metabolismoRESUMEN
This study investigated the effects of exercise training on cardiac inflammatory and cardiac fibrotic pathways in female spontaneously hypertensive rats (SHR), which were divided into a sham-operated sedentary hypertensive group (SHR-S), a sedentary hypertensive ovariectomized group (SHR-O), or a hypertensive ovariectomized group with treadmill exercise training (SHR-OT; 60 min/day, 5 days/wk) for 8 wk. Normotensive female Wistar-Kyoto rats (WKY) served as controls. SOD and catalase (CAT) activities were significantly increased in the SHR-OT group, when compared with the SHR-S or SHR-O groups. The protein levels of estrogen receptor (ER)-α and ER-ß became decreased in the SHR-O group, when compared with the WKY or SHR-S groups, but were not changed in the SHR-OT group. The protein level of the angiotensin II type I receptor (AT1R) was increased in the SHR-S group but did not further change in the SHR-O group, whereas it was decreased in the SHR-OT group. The inflammatory-related protein levels of TNF-α, p-NF-κB, cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), and IL-6, as well as the fibrotic-related protein levels of transforming growth factor-ß (TGF-ß), p-Smad2/3, connective tissue growth factor (CTGF), tissue-type plasminogen activator (tPA), matrix metalloproteinase (MMP)-9, and collagen I were increased in the SHR-S group and increased further in the SHR-O group, whereas they were decreased in the SHR-OT group. The coexistence of hypertension and ovariectomy additively increased cardiac inflammatory and fibrotic pathways partially through hypertension-enhanced AT1R and ovariectomy-depressed estrogen receptors. Exercise training appeared to suppress hypertensive ovariectomized heart-induced inflammatory and fibrotic pathways possibly through decreasing AT1R but not through estrogen receptors.NEW & NOTEWORTHY The coexistence of hypertension and ovariectomy appeared to increase cardiac inflammatory and fibrotic pathways likely through hypertension-enhanced angiotensin II type I receptor and ovariectomy-depressed estrogen receptors. Exercise training on a treadmill could prevent hypertensive ovariectomized heart-induced cardiac inflammation and fibrosis via an inflammatory pathway [TNF-α, p-IKK-α/ß, p-NF-κB, cyclooxygenase 2 (COX-2), iNOS, and IL-6] and fibrotic pathway [transforming growth factor-ß (TGF-ß), p-Smad2/3, connective tissue growth factor (CTGF), tissue-type plasminogen activator (tPA), matrix metalloproteinase (MMP)-9, and collagen I] possibly through decreasing angiotensin II type I receptor but not through estrogen receptors.
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Hipertensión , Miocardio , Animales , Presión Sanguínea , Femenino , Fibrosis , Hipertensión/patología , Inflamación/patología , Miocardio/patología , Ratas , Ratas Endogámicas WKYRESUMEN
Protocatechuic acid (PCA), a strong antioxidant, has been reported for its cardiovascular-protective effects. This study aimed to investigate the effects of PCA administration on vascular endothelial function, mediated by insulin and insulin-like growth factor-1 (IGF-1), and antioxidant activities in aging hypertension. Thirty-six-week-old male aging spontaneously hypertensive rats were randomly divided into vehicle control (SHR) and PCA (SHR+PCA) groups, while age-matched Wistarâ»Kyoto rats (WKY) served as the normotensive vehicle control group. The oral PCA (200 mg/kg/day) was administered daily for a total of 12 weeks. When the rats reached the age of 48 weeks, the rat aortas were isolated for the evaluation of vascular reactivity and Western blotting. Also, nitric oxide (NO) production and antioxidant activities were examined among the three groups. The results showed that, when compared with the SHR group, the insulin-induced and IGF-1-induced vasorelaxation were significantly improved in the SHR+PCA group. There was no significant difference in the endothelium-denuded vessels among the three groups. After the pre-incubation of phosphatidylinositol 3-kinase (PI3K) or NO synthase (NOS) inhibitors, the vasorelaxation was abolished and comparable among the three groups. The protein levels of insulin receptors, IGF-1 receptors, phospho-protein kinase B (p-Akt)/Akt, and phospho-endothelial NOS (p-eNOS)/eNOS in aortic tissues were significantly enhanced in the SHR+PCA group when compared with the SHR group. Moreover, significant improvements of nitrate/nitrite concentration and antioxidant activities, including superoxide dismutase, catalase, and total antioxidants, were also found in the SHR+PCA group. In conclusion, the 12 weeks of PCA administration remarkably improved the endothelium-dependent vasorelaxation induced by insulin and IGF-1 in aging hypertension through enhancing the PI3Kâ»NOSâ»NO pathway. Furthermore, the enhanced antioxidant activities partly contributed to the improved vasorelaxation.
Asunto(s)
Envejecimiento , Hidroxibenzoatos/farmacología , Insulina/farmacología , Vasodilatación/efectos de los fármacos , Animales , Antioxidantes/farmacología , Aorta/efectos de los fármacos , Aorta/metabolismo , Presión Sanguínea/efectos de los fármacos , Suplementos Dietéticos , Regulación de la Expresión Génica/efectos de los fármacos , Frecuencia Cardíaca , Humanos , Hidroxibenzoatos/administración & dosificación , Factor I del Crecimiento Similar a la Insulina , Masculino , Polienos , Distribución Aleatoria , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
This study was to investigate the effects of exercise training on antiapoptotic pathways and mitochondrial biogenesis in ovariectomized hypertensive rats. Histopathological analysis, TUNEL assay, and Western blotting were performed on the excised hearts from female spontaneously hypertensive rats (SHR), which were divided into a sham-operated sedentary hypertensive (SHR-S), a sedentary hypertensive ovariectomized (SHR-O), and hypertensive ovariectomized rats that underwent treadmill exercise training (SHR-OT; 60 min/day, 5 days/wk) for 8 wk, along with normotensive Wistar Kyoto rats (WKY). When compared with the WKY group, the SHR-S group exhibited decreased protein levels of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial OPA-1 (mitochondrial biogenesis) and decreased further in the SHR-O group. The protein levels of p-PI3K, p-Akt, Bcl-2, Bcl-xL (prosurvival pathways), and the protein levels of PGC-1α and mitochondrial OPA1 (mitochondrial biogenesis) were increased in the SHR-OT group, but estrogen receptor (ER)α and ERß were not changed when compared with the SHR-O group. The protein levels of t-Bid, Bad, Bax, cytosolic cytochrome c, activated caspase 9, and activated caspase 3 (mitochondria-dependent apoptotic pathways), as well as Fas ligand, TNF-α, Fas receptors, Fas-associated death domain, activated caspase 8 (Fas receptor-dependent apoptotic pathways) were decreased in the SHR-OT group, when compared with the SHR-O group. Exercise training protection on the coexistence of hypertension and ovariectomy-induced cardiac mitochondria-dependent and Fas receptor-dependent apoptotic pathways by enhancing the Bcl2-related and mitochondrial biogenetic prosurvival pathways might provide a new therapeutic effect on cardiac protection in oophorectomized early postmenopausal hypertensive women. NEW & NOTEWORTHY Widely dispersed cardiac apoptosis was found in the coexistence of hypertension and ovariectomy. Exercise training on a treadmill could prevent ovariectomized hypertension-induced widely dispersed cardiac apoptosis via mitochondria-dependent apoptotic pathway (t-Bid, Bad, Bax, cytosolic cytochrome c, activated caspase 9, and activated caspase 3) and Fas receptor-dependent apoptotic pathway (Fas ligand, tumor necrosis factor-α, Fas receptors, Fas-associated death domain, activated caspase 8, and activated caspase 3) through enhancing the Bcl2-related (p-PI3K, p-Akt, Bcl-2, Bcl-xL) and mitochondrial biogenetic (PGC-1α and mitochondrial optic atrophy 1) prosurvival pathways.
Asunto(s)
Apoptosis/fisiología , Corazón/fisiopatología , Hipertensión/fisiopatología , Mitocondrias Cardíacas/fisiología , Condicionamiento Físico Animal/fisiología , Animales , Presión Sanguínea/fisiología , Caspasas/metabolismo , Proteína Ligando Fas/metabolismo , Femenino , Hipertensión/metabolismo , Mitocondrias Cardíacas/metabolismo , Miocardio/metabolismo , Biogénesis de Organelos , Ovariectomía/métodos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Transducción de Señal/fisiología , Receptor fas/metabolismoRESUMEN
BACKGROUND: The purpose of this study was to investigate the combined 17ß-estradiol (E2) and exercise training on cardiac pro-survival and anti-apoptotic pathways in ovariectomized rats. METHODS: Fifty-six female Sprague-Dawley rats were divided into a sham-operated (Sham), a bilaterally ovariectomized (OVX), an OVX treated with E2 (OVX-E2; 10µg/kg/day), and an OVX with E2 and treadmill exercise training (OVX-E2-EX; 60 min/day, 5 days/week) for 10 weeks. Following 10 weeks of exercise training, rat hearts were isolated for the evaluation of Histopathological analysis, TUNEL assay, and Western blotting. RESULTS: The protein levels of estrogen receptor α (ERα), estrogen receptor ß (ERß), insulin-like growth factor 1 (IGF-1), IGF-1 receptor (IGF-1R), phospho-phosphatidylinositol 3-kinase (p-PI3K) (estrogen receptors/IGF-1-related survival pathway) were significantly increased in either the OVX-E2 or OVX-E2-EX group when compared with the OVX group. The protein levels of B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra-large (Bcl-xL) and phosphorylated-Bad (p-Bad) (Bcl-2 family survival pathway) were significantly increased in the OVX-E2-EX group when compared with the OVX group. Only the p-Bad was significantly increased in the OVX-E2 group when compared with the OVX group. The protein levels of truncation of Bid (t-Bid), Bcl-2-associated death promotor (Bad), Bcl-2-associated X protein (Bax), Cytochrome c, caspases-9, and caspases-3 (mitochondria-dependent apoptotic pathway), as well as the protein levels of tumor necrosis factor-α (TNF-α), Fas ligand, Fas receptors, Fas-associated death domain (FADD), activated caspase-8 and activated caspase-3 (Fas receptor-dependent apoptotic pathway) were significantly decreased in either the OVX-E2 or OVX-E2-EX group when compared with the OVX group. Furthermore, when compared with the OVX-E2 group, the protein levels of ERß, IGF-1, IGF-1R, Bcl-2 and Bcl-xL were further enhanced in the OVX-E2-EX group as well as the protein levels of Cytochrome c, Fas receptors, FADD, activated caspase-8, activated caspase-9 and activated caspase-3 were further decreased in the OVX-EX-E2 group. CONCLUSIONS: Combined E2 and exercise training exhibited a positive effect of protection on ovariectomy-induced cardiac apoptosis by enhancing ERß-related survival pathways, which might provide a more effective therapeutic effect on cardiac protection in bilaterally oophorectomized or menopausal women than E2 treatment only.