RESUMO
Long-term ß-adrenoceptor (ß-AR) stimulation is a pathological mechanism associated with cardiovascular diseases resulting in endothelial and perivascular adipose tissue (PVAT) dysfunction. In this study, we aimed to identify whether ß-adrenergic signaling has a direct effect on PVAT. Thoracic aorta PVAT was obtained from male Wistar rats and cultured ex vivo with the ß-AR agonist isoproterenol (Iso; 1â µM) or vehicle for 24 hours. Conditioned culture medium (CCM) from Iso-treated PVAT induced a marked increase in aorta contractile response, induced oxidative stress, and reduced nitric oxide production in PVAT compared to vehicle. In addition, Iso-treated PVAT and PVAT-derived differentiated adipocytes exhibited higher corticosterone release and protein expression of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), an enzyme responsible for de novo synthesis of corticosterone. Macrophages exposed to Iso also exhibited increased corticosterone release in response to ß-AR stimulation. Incubation of Iso-treated PVAT and PVAT-derived differentiated adipocytes with ß3-AR antagonist restored aorta contractile function modulated by Iso-CCM and normalized 11ß-HSD1 protein expression. These results show that ß3-AR signaling leads to upregulation of 11ß-HSD1 in PVAT, thus increasing corticosterone release and contributing to impair the anticontractile function of this tissue.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1 , Corticosterona , Isoproterenol , Animais , Masculino , Ratos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Adipócitos/metabolismo , Adipócitos/efeitos dos fármacos , Tecido Adiposo/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Corticosterona/metabolismo , Meios de Cultivo Condicionados/farmacologia , Isoproterenol/farmacologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Receptores Adrenérgicos beta/metabolismoRESUMO
The purpose of this study was to investigate the effect of an egg white hydrolysate (EWH) to protect white adipose tissue damage from cardiometabolic changes induced by severe hypertension. Male Wistar rats were uninephrectomised and divided: SHAM (weekly subcutaneous vehicle (mineral oil + propylene glycol, 1:1)), SHAM + EWH (subcutaneous vehicle plus EWH via gavage, 1 g/kg per day), DOCA (deoxycorticosterone acetate diluted in vehicle subcutaneously weekly in subsequent doses of 20 mg/kg -1st week, 12 mg/kg - 23th week, and 6 mg/kg -48th week, respectively, plus 1 % NaCl and 0·2 % KCl in drinking water), and DOCA + EWH. Body weight gain, food and water intake, glucose and lipid metabolism were evaluated. Oxidative stress was assessed by biochemical assay and immunofluorescence for NOX-1, nuclear factor kappa B (NFκB), and caspase-3 in retroperitoneal white adipose tissue (rtWAT). Proinflammatory cytokines (IL-6 and 1ß), CD163+ macrophage infiltration, and immunohistochemistry for TNFα and uncoupling protein-1 were evaluated, as well as histological analysis on rtWAT. Glutathione peroxidase and reductase were also determined in plasma. EWH showed hypocholesterolemic, antioxidant, anti-inflammatory, and anti-apoptotic properties in the arterial hypertension DOCA-salt model. The results demonstrated the presence of functional changes in adipose tissue function by a decrease in macrophage infiltration and in the fluorescence intensity of NFκB, NOX-1, and caspase-3. A reduction of proinflammatory cytokines and restoration of antioxidant enzymatic activity and mitochondrial oxidative damage by reducing uncoupling protein-1 fluorescence intensity were also observed. EWH could be used as a potential alternative therapeutic strategy in the treatment of cardiometabolic complications associated with malignant secondary arterial hypertension.
Assuntos
Tecido Adiposo Branco , Acetato de Desoxicorticosterona , Clara de Ovo , Estresse Oxidativo , Ratos Wistar , Animais , Masculino , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Clara de Ovo/química , Ratos , Hipertensão/metabolismo , Hipertensão/induzido quimicamente , Hidrolisados de Proteína/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Proteína Desacopladora 1/metabolismo , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/efeitos dos fármacosRESUMO
The essential role of the endothelium in vascular homeostasis is associated with the release of endothelium-dependent relaxing and contractile factors (EDRF and EDCF, respectively). Different from arteries, where these factors are widely studied, the vasoactive factors derived from the venous endothelium have been given less attention. There is evidence for a role of the nitric oxide (NO), endothelium-dependent hyperpolarization (EDH) mechanism, and cyclooxygenase (COX)-derived metabolites as EDRFs; while the EDCFs need to be better evaluated since no consensus has been reached about their identity in venous vessels. The imbalance between the synthesis, bioavailability, and/or action of EDRFs and/or EDCFs results in a pathological process known as endothelial dysfunction, which leads to reduced vasodilation and/or increased vasoconstriction. In the venous system, endothelial dysfunction is relevant since reduced venodilation may increase venous tone and decrease venous compliance, thus enhancing mean circulatory filling pressure, which maintains or modify cardiac workload contributing to the etiology of cardiovascular diseases. Interestingly, some alterations in venous function appear at the early stages (or even before) the establishment of these diseases. However, if the venous endothelium dysfunction is involved in these alterations is not yet fully understood and requires further studies. In this sense, the present study aims to review the current knowledge on venous endothelial function and dysfunction, and the general state of the venous tone in two important cardiovascular diseases of high incidence and morbimortality worldwide: hypertension and heart failure.
Assuntos
Doenças Cardiovasculares , Hipertensão , Humanos , Doenças Cardiovasculares/metabolismo , Endotélio Vascular/metabolismo , Vasodilatação , Vasoconstrição , Óxido Nítrico/metabolismoRESUMO
During hypertension an unbalance of short-chain fatty acids (SCFAs) production by intestinal bacteria is described. However, no data evaluate the association of SCFAs and vascular remodeling in hypertension, which is an important hallmark of this disease. Thus, the present study aims to evaluate the correlations between SCFAs availability and the resistance arteries remodeling in hypertension, as well as to identify the possible pathway by which the SCFAs could exert a structural and mechanical influence. Hence, male spontaneously hypertensive rats (SHR) and normotensive Wistar rats had blood pressure measured by tail-cuff plethysmography; fecal SCFAs content assessed by gas chromatography; gene expression of SCFAs-transporters in gut epithelium and SCFAs-sensing receptors on mesenteric resistance arteries (MRA) quantified by PCR; and MRA structural and mechanical parameters analyzed by pressure myograph. Reduced butyrate fecal content was found in SHR, with no changes in propionate and acetate, as well as decreased mRNA levels of SCFAs-transporters (MCT1, MCT4, and SMCT1) in the intestinal epithelium. In addition, lower gene expression of SCFAs-sensing receptors (GPR41, GPR43, and GPR109a, but not Olfr78) was identified in MRAs of SHR, which also shows inward eutrophic remodeling with stiffness. Butyrate content presented a negative correlation with systolic blood pressure and with the structural alterations found on MRAs, while a positive correlation between butyrate content and mechanical parameters was detected. Altogether the present study suggests that lower butyrate content due to ineffective SCFA bioavailability, associated with lower SCFAs-sensing receptors expression, could favor MRA remodeling, increasing peripheral vascular resistance and worsening hypertension prognosis.
RESUMO
This study aimed to evaluate the potential for lowering blood pressure and beneficial effects on mesenteric resistance arteries (MRA) and conductance vessels (aorta) produced by dietary supplementation of an egg white hydrolysate (EWH) in rats with severe hypertension induced by deoxycorticosterone plus salt treatment (DOCA-salt), as well as the underlying mechanisms involved. The DOCA-salt model presented higher blood pressure, which was significantly reduced by EWH. The impaired acetylcholine-induced relaxation and eNOS expression observed in MRA and aorta from DOCA-salt rats was ameliorated by EWH. This effect on vessels (MRA and aorta) was related to the antioxidant effect of EWH, since hydrolysate intake prevented the NF-κB/TNFα inflammatory pathway and NADPH oxidase-induced reactive oxygen species (ROS) generation, as well as the mitochondrial source of ROS in MRA. At the plasma level, EWH blocked the higher ROS and MDA generation by DOCA-salt treatment, without altering the antioxidant marker. In conclusion, EWH demonstrated an antihypertensive effect in a model of severe hypertension. This effect could be related to its endothelium-dependent vasodilator properties mediated by an ameliorated vessel's redox imbalance and inflammatory state.
RESUMO
AIM: Endothelial mechanisms underlying the vascular effects of estrogen modulated by the G protein-coupled estrogen receptor (GPER) are not well understood, especially in gonadal sex hormone deprivation. Thus, we investigated vascular function and endothelial signaling pathways involved in the selective activation of GPER in resistance arteries of gonadectomized rats. METHODS: Gonadectomy was performed in Wistar rats of both sexes. After 21 days, the animals were euthanized. Concentration-response curves were obtained by cumulative additions of G-1 in third-order mesenteric arteries. The vasodilatory effects of G-1 were evaluated before and after endothelium removal or incubation with pharmacological inhibitors. Tissue protein expression was measured by western blotting. Assays with 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM) and 2',7' dichlorodihydrofluorescein-diacetate (H2DCF-DA) were performed in the arteries investigated. Immunolocalization was assessed by immunofluorescence. RESULTS: G-1 induced partially endothelium-dependent relaxation in both sexes. The three isoforms of the enzyme nitric oxide synthase contributed to the production and release of nitric oxide in both gonadectomized groups, but the role of inducible nitric oxide synthase is more expressive in males. The mechanistic pathway by which endothelial nitric oxide synthase is phosphorylated appears to differ between sexes, with the rapid signaling pathway phosphatidylinositol-3-kinase/protein kinase B/endothelial nitric oxide synthase (PI3k-Akt-eNOS) being identified for males and mitogen-activated protein kinase/extracellular signal-regulated kinase/endothelial nitric oxide synthase (MEK-ERK-eNOS) for females. The contribution of hydrogen peroxide as an endothelial relaxation mediator seems to be greater in females. CONCLUSION: These results provide new insights into the effects of estrogen-induced responses via GPER on vascular function in gonadal sex hormone deprivation.
Assuntos
Óxido Nítrico Sintase Tipo III , Proteínas Proto-Oncogênicas c-akt , Animais , Endotélio Vascular , Estrogênios/metabolismo , Estrogênios/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Proteínas de Ligação ao GTP/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Peróxido de Hidrogênio/metabolismo , Masculino , Artérias Mesentéricas , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositóis/metabolismo , Fosfatidilinositóis/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Caracteres Sexuais , Transdução de Sinais , Vasodilatadores/farmacologiaRESUMO
Arterial endothelial dysfunction has been extensively studied in heart failure (HF). However, little is known about the adjustments shown by the venous system in this condition. Considering that inferior vena cava (VC) tone could influence cardiac performance and HF prognosis, the aim of the present study was to assess the VC and thoracic aorta (TA) endothelial function of HF-post-myocardial infarction (MI) rats, comparing both endothelial responses and signaling pathways developed. Vascular reactivity of TA and VC from HF post-MI and sham operated (SO) rats was assessed with a wire myograph, 4 weeks after coronary artery occlusion surgery. Nitric oxide (NO), H2O2 production and oxidative stress were evaluated in situ with fluorescent probes, while protein expression and dimer/monomer ratio was assessed by Western blot. VC from HF rats presented endothelial dysfunction, while TA exhibited higher acetylcholine (ACh)-induced vasodilation when compared with vessels from SO rats. TA exhibited increased ACh-induced NO production due to a higher coupling of endothelial and neuronal NO synthases isoforms (eNOS, nNOS), and enhanced expression of antioxidant enzymes. These adjustments, however, were absent in VC of HF post-MI rats, which exhibited uncoupled nNOS, oxidative stress and higher H2O2 bioavailability. Altogether, the present study suggests a differential regulation of endothelial function between VC and TA of HF post-MI rats, most likely due to nNOS uncoupling and compromised antioxidant defense.
Assuntos
Aorta Torácica/fisiopatologia , Endotélio Vascular/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Óxido Nítrico Sintase/metabolismo , Veia Cava Inferior/fisiopatologia , Animais , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Peróxido de Hidrogênio/metabolismo , Masculino , Infarto do Miocárdio/complicações , Estresse Oxidativo , Ratos Wistar , Veia Cava Inferior/enzimologiaRESUMO
AIM: Previous studies raise cyclooxygenase (COX) activation as a possible mechanism involved in the pathophysiology of ouabain-induced hypertension. We hypothesized that inhibition of COX-2 activity might prevent ouabain-induced vascular dysfunction and worsening of hypertension in spontaneously hypertensive rats (SHR). METHODS: SHR were exposed to ouabain or vehicle and treated or not with the selective COX-2 inhibitor nimesulide for 5 weeks. Systolic blood pressure was measured by plethysmography. Vascular reactivity by wire myograph and protein expression by Western-blot were assessed in mesenteric resistance arteries (MRA) of groups. Thromboxane A2 (TXA2) production by ELISA was evaluated in MRA supernatants of groups. RESULTS: Noradrenaline-induced maximal contraction (Emax) was greater in MRA from SHR receiving ouabain than those of vehicle group. In situ inhibition of COX-2, TXA2 synthase, or TP receptor reduced the Emax to noradrenaline in MRA of ouabain to vehicle levels. TXA2 production was higher in ouabain than in vehicle group. Ouabain enhanced expression of cytoplasmic tyrosine kinase Src (c-Src)/ERK1/2/COX-2/TXA2 synthase/TP receptor in SHR MRA, but did not change NFkB/iKB ratio. Anticontractile effect of nitric oxide (NO) was smaller in MRA from ouabain- than vehicle-treated SHR, as well as eNOS and nNOS expression. Nimesulide co-treatment prevented the ouabain-induced worsening of hypertension and noradrenaline MRA hypercontractility in SHR. CONCLUSION: Ouabain worsen hypertension and induce MRA hypercontractility in SHR associated with upregulated c-Src/ERK1/2/COX-2/TXA2 synthase/TXA2/TP receptor axis. These effects were prevented by COX-2 inhibition.
Assuntos
Hipertensão , Ouabaína , Animais , Pressão Sanguínea , Ciclo-Oxigenase 2/metabolismo , Endotélio Vascular , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/prevenção & controle , Artérias Mesentéricas/metabolismo , Ouabaína/farmacologia , Ratos , Ratos Endogâmicos SHR , Vasoconstrição , VasodilataçãoRESUMO
Perivascular adipose tissue (PVAT) dysfunction is associated with vascular damage in cardiometabolic diseases. Although heart failure (HF)-induced endothelial dysfunction is associated with renin-angiotensin system (RAS) activation, no data have correlated this syndrome with PVAT dysfunction. Thus, the aim of the present study was to investigate whether the hyperactivation of the RAS in PVAT participates in the vascular dysfunction observed in rats with HF after myocardial infarction surgery. Wire myograph studies were carried out in thoracic aorta rings in the presence and absence of PVAT. An anticontractile effect of PVAT was observed in the rings of the control rats in the presence (33%) or absence (11%) of endothelium. Moreover, this response was substantially reduced in animals with HF (5%), and acute type 1 angiotensin II receptor (AT1R) and type 2 angiotensin II receptor (AT2R) blockade restored the anticontractile effect of PVAT. In addition, the angiotensin-converting enzyme 1 (ACE1) activity (26%) and angiotensin II levels (51%), as well as the AT1R and AT2R gene expression, were enhanced in the PVAT of rats with HF. Associated with these alterations, HF-induced lower nitric oxide bioavailability, oxidative stress and whitening of the PVAT, which suggests changes in the secretory function of this tissue. The ACE1/angiotensin II/AT1R and AT2R axes are involved in thoracic aorta PVAT dysfunction in rats with HF. These results suggest PVAT as a target in the pathophysiology of vascular dysfunction in HF and provide new perspectives for the treatment of this syndrome.
Assuntos
Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Sistema Renina-Angiotensina , Angiotensina II/metabolismo , Animais , Aorta Torácica/patologia , Disponibilidade Biológica , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Insuficiência Cardíaca/complicações , Hemodinâmica , Masculino , Modelos Biológicos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/fisiopatologia , Óxido Nítrico/metabolismo , Estresse Oxidativo , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , VasoconstriçãoRESUMO
BACKGROUND: Accumulated evidence shows that the ACE-AngII-AT1 axis of the renin-angiotensin system (RAS) is markedly activated in chronic heart failure (CHF). Recent studies provide information that Angiotensin (Ang)-(1-7), a metabolite of AngII, counteracts the effects of AngII. However, this balance between AngII and Ang-(1-7) is still little understood in CHF. We investigated the effects of exercise training on circulating and skeletal muscle RAS in the ischemic model of CHF. METHODS/MAIN RESULTS: Male Wistar rats underwent left coronary artery ligation or a Sham operation. They were divided into four groups: 1) Sedentary Sham (Sham-S), 2) exercise-trained Sham (Sham-Ex), sedentary CHF (CHF-S), and exercise-trained CHF (CHF-Ex). Angiotensin concentrations and ACE and ACE2 activity in the circulation and skeletal muscle (soleus and plantaris) were quantified. Skeletal muscle ACE and ACE2 protein expression, and AT1, AT2, and Mas receptor gene expression were also evaluated. CHF reduced ACE2 serum activity. Exercise training restored ACE2 and reduced ACE activity in CHF. Exercise training reduced plasma AngII concentration in both Sham and CHF rats and increased the Ang-(1-7)/AngII ratio in CHF rats. CHF and exercise training did not change skeletal muscle ACE and ACE2 activity and protein expression. CHF increased AngII levels in both soleus and plantaris muscle, and exercise training normalized them. Exercise training increased Ang-(1-7) in the plantaris muscle of CHF rats. The AT1 receptor was only increased in the soleus muscle of CHF rats, and exercise training normalized it. Exercise training increased the expression of the Mas receptor in the soleus muscle of both exercise-trained groups, and normalized it in plantaris muscle. CONCLUSIONS: Exercise training causes a shift in RAS towards the Ang-(1-7)-Mas axis in skeletal muscle, which can be influenced by skeletal muscle metabolic characteristics. The changes in RAS circulation do not necessarily reflect the changes occurring in the RAS of skeletal muscle.