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1.
Toxicol Lett ; 333: 130-139, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32763311

RESUMO

Trichloroethylene (TCE) is a widely used industrial solvent that causes trichloroethylene hypersensitivity syndrome (THS) with multi-system damage, including kidney injury. Clinical studies have shown that the complement system is important for TCE-induced kidney injury. Our previous study found excessive deposition of complement C3, mainly on the glomerulus, indicating that local renal complement is activated after TCE sensitisation. However, whether local renal complement activation mediates TCE-induced immune kidney injury and the underlying mechanisms remain unknown. Therefore, we established a TCE percutaneous sensitisation BALB/c mouse model to explore the mechanisms by pretreating with or without the complement activation antagonist, cathepsin L inhibitor (CatLi). As expected, more C3 and C3a were detected mainly on glomerulus of TCE positive sensitisation (TCE+) mice. Renal dysfunction and pathological damage were also clearly observed in TCE+ mice. Moreover, the mRNA and protein expression of ET-1 increased significantly with local renal complement activation after TCE sensitisation, leading to cytokines release and inflammation. In addition, activation of p38MAPK and NF-κBp65 pathways were detected in kidneys of TCE+ mice, and CatLi pretreatment decreased these changes through complement activation antagonisation. Our research uncovered a novel role of local renal complement activation during immune kidney injury after TCE sensitisation through induction of ET-1 signalling and inflammation.


Assuntos
Ativação do Complemento/imunologia , Endotelina-1/metabolismo , Hipersensibilidade/metabolismo , Rim/efeitos dos fármacos , Insuficiência Renal/metabolismo , Tricloroetileno/toxicidade , Animais , Ativação do Complemento/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Hipersensibilidade/imunologia , Inflamação , Rim/imunologia , Rim/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/efeitos dos fármacos , NF-kappa B/imunologia , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/imunologia , Transdução de Sinais
2.
Life Sci ; 258: 118223, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768584

RESUMO

Kidney fibrosis is a common final pathway of chronic kidney diseases, which are characterized by renal architecture damage, inflammation, fibroblast expansion and myofibroblast formation. Endothelin converting enzyme-1 (ECE-1) contributes to activation of Endothelin-1 (ET-1), a potent vasoconstrictor and pro-fibrotic substance. This study elucidated the effect of ECE-1 knockout in kidney fibrosis model in mice in association of ET-1 downregulation. Kidney fibrosis was performed in ECE-1 knockout (ECE-1 KO) and vascular endothelial derived ET-1 KO (VEETKO) mice (2 months, 20-30 g, n = 30) and their wild type (WT) littermates using unilateral ureteral obstruction (UUO) procedure. Mice were euthanized on day-7 and day-14 after UUO. Histopathological analysis was conducted for fibrosis and tubular injury. Immunostainings were done to quantify macrophages (F4/80), fibroblasts (FSP-1) and myofibroblasts (α-SMA). Monocyte Chemoattractant Protein-1 (MCP-1), ECE-1 and preproET-1 (ppET-1) mRNA expression were quantified with qRT-PCR, while Transforming Growth Factor-ß1 (TGF-ß1) and α-SMA protein level were quantified with Western blot. ECE-1 KO mice demonstrated reduction of ECE-1 and ppET-1 mRNA expression, attenuation of kidney fibrosis, tubular injury, MCP-1 mRNA expression and macrophage number compared to WT. Double immunostaining revealed fibroblast to myofibroblast formation after UUO, while ECE-1 KO mice had significantly lower fibroblast number and myofibroblast formation compared to WT, which were associated with significantly lower TGF-ß1 and α-SMA protein levels in day-14 of UUO. VEETKO mice also demonstrated attenuation of ET-1 protein level, fibrosis and myofibroblast formation. In conclusion, ECE-1 knockout and ET-1 downregulation attenuated kidney fibrosis.


Assuntos
Regulação para Baixo/fisiologia , Endotelina-1/metabolismo , Enzimas Conversoras de Endotelina/deficiência , Rim/metabolismo , Animais , Enzimas Conversoras de Endotelina/genética , Fibrose , Rim/patologia , Masculino , Camundongos , Camundongos Knockout
3.
Medicine (Baltimore) ; 99(24): e20253, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541451

RESUMO

This study is to explore the molecular mechanism of benign bile duct hypertrophic scar formation.Differential proteins between the normal fibroblast (NFB) and scar fibroblast (SCFB) were screened by protein chip assay, and analyzed by pathway-enrichment analysis and function-enrichment analysis. The differential proteins were further tested by ELISA. SiRNA-Act B was transfected to SCFB to down-regulate the expression of Act B. NFB was incubated with rh-Act B. The cell apoptosis and cell cycle were determined by flow cytometry. The expression of Act B, Smad2/3, transforming growth factor-ß1 (TGF-ß1), endothelin-1 (ET-1), thrombospondin-1 (Tsp-1), and Oncostatin M (OSM) were detected by Western blot.A total of 37 differential proteins were identified in SCFBs by microarray (P < .05), including 27 up-regulated proteins and 10 down-regulated proteins (P < .05). Their function were associated with Activin signaling, synthesis and degradation of extracellular matrix, formation and activation of cytokine, inflammatory reaction, immunoreaction, tissue damage reaction, cell cycle, migration, apoptosis, and secretion, etc. ELISA results showed that the expression of Act B, TGF-ß1, ET-1 were higher in SCFBs, while the expression of Tsp-1 and OSM were lower in SCFBs (P < .05). After interfered by siRNA-Act B, the expression of Act B mRNA decreased (P < .05). The percentage of early apoptosis increased (P < .05). The expression of Act B, Smad2/3, TGF-ß1 were decreased and Tsp-1, OSM were increased (P < .05). After treatment with rh-Act B, the percentage of G0/G1 phase of NFBs was decreased and that of S phase was increased without significance (P > .05). The expression of Act B, Smad2/3, TGF-ß1 were increased (P < .05) and Tsp-1, OSM were decreased (P < .01).There are differentially expressed proteins between SCFBs and NFBs. Activin B signal plays an important role in the process of NFB transforming to SCFB, and TGF-ß1, Smad2/3, Tsp-1, and OSM are important participants.


Assuntos
Ativinas/metabolismo , Ductos Biliares/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Transdução de Sinais/fisiologia , Adulto , Apoptose/fisiologia , Ciclo Celular/fisiologia , Cicatriz Hipertrófica , Endotelina-1/metabolismo , Matriz Extracelular/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oncostatina M/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Proteína Smad2/metabolismo , Trombospondina 1/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
4.
Nat Commun ; 11(1): 2138, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358570

RESUMO

Signaling molecules that regulate neurodevelopmental processes in the early postnatal subventricular zone (SVZ) are critical for proper brain development yet remain poorly characterized. Here, we report that Endothelin-1 (ET-1), a molecular component of the postnatal SVZ, promotes radial glial cell maintenance and proliferation in an autocrine manner via Notch signaling. Loss of ET-1 signaling increases neurogenesis and reduces oligodendrocyte progenitor cell proliferation (OPC) in the developing SVZ, thereby altering cellular output of the stem cell niche. We also show that ET-1 is required for increased neural stem cell and OPC proliferation in the adult mouse SVZ following demyelination. Lastly, high levels of ET-1 in the SVZ of patients with Cathepsin A-related arteriopathy with strokes and leukoencephalopathy correlate with an increased number of SVZ OPCs, suggesting ET-1's role as a regulator of glial progenitor proliferation may be conserved in humans. ET-1 signaling therefore presents a potential new therapeutic target for promoting SVZ-mediated cellular repair.


Assuntos
Endotelina-1/metabolismo , Sistema Nervoso/citologia , Sistema Nervoso/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Nicho de Células-Tronco/fisiologia , Animais , Proliferação de Células/fisiologia , Endotelina-1/genética , Humanos , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/fisiologia , Nicho de Células-Tronco/genética
5.
PLoS One ; 15(4): e0230665, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32251485

RESUMO

Phagocytes in patients with chronic granulomatous disease (CGD) do not generate reactive oxidative species (ROS), whereas nitric oxide (NO) production is increased in response to the calcium ionophore A23187 in CGD phagocytes compared with healthy phagocytes. Recently, patients with X-linked CGD (X-CGD) have been reported to show higher flow-mediated dilation, suggesting that endothelial cell function is affected by NO production from phagocytes. We studied NOS3 and EDN1 mRNA and protein expression in human umbilical vein endothelial cells (HUVECs) in a co-culture system with neutrophils from X-CGD patients. HUVECs were co-cultured for 30 minutes with human neutrophils from X-CGD or healthy participants in response to A23187 without cell-to-cell contact. The expression of NOS3 and EDN1 mRNA in HUVECs was quantified by real-time polymerase chain reaction. Moreover, we demonstrated the protein expression of eNOS, ET-1, and NFκB p65, including phosphorylation at Ser1177 of eNOS and Ser536 of NFκB p65. Neutrophils from X-CGD patients showed significantly higher NO and lower H2O2 production in response to A23187 than healthy neutrophils in vitro. Compared with healthy neutrophils, X-CGD neutrophils under A23187 stimulation exhibited significantly increased NO and decreased H2O2, and promoted downregulated NOS3 and EDN1 expression in HUVECs. The total expression and phosphorylation at Ser1177 of eNOS and ET-1 expression were significantly decreased in HUVECs co-cultures with stimulated X-CGD neutrophils. Also, phosphorylation at Ser536 of NFκB p65 were significantly decreased. In conclusions, eNOS and ET-1 significantly down-regulated in co-culture with stimulated X-CGD neutrophils through their excessive NO and the lack of ROS production. These findings suggest that ROS generated from neutrophils may mediate arterial tone affecting eNOS and ET-1 expression via their NO and ROS production.


Assuntos
Técnicas de Cocultura , Regulação para Baixo , Endotelina-1/metabolismo , Doença Granulomatosa Crônica/metabolismo , Neutrófilos/citologia , Neutrófilos/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Adolescente , Estudos de Casos e Controles , Endotelina-1/genética , Feminino , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/imunologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Masculino , Óxido Nítrico Sintase Tipo III/genética , Fosforilação , RNA Mensageiro/genética , Fator de Transcrição RelA/metabolismo
6.
Sci Rep ; 10(1): 4073, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139801

RESUMO

Lipopolysaccharide (LPS) induces fever through cytokines like receptor-activator of nuclear factor κB ligand (RANKL), triggering mediators like prostaglandins (PG), endothelin-1 (ET-1), corticotrophin-releasing factor (CRF), substance P (SP) and endogenous opioids. LPS-induced fever is reduced in females compared with males except in ovariectomized (OVX) females which show increased fever mediated by PG. The present study aimed to identify the mediators involved in fever in intact and OVX female rats. Fever was induced with LPS (50 µg/kg) intraperitoneally or CRF (2.5 µg), ET-1 (1 pg), morphine (10 µg) and SP (500 ng) intracerebroventricularly in sham-operated and OVX rats. The role of RANKL was evaluated with osteoprotegerin (OPG, 1 µg, intracerebroventricularly). Expression of RANK, CRFI/II, ETB, µ-opioid (MOR) and NK1 receptors was evaluated by confocal microscopy. Besides LPS, only morphine induced fever in OVX rats while all mediators induced fever in sham-operated animals. OPG abolished LPS-induced fever in OVX but not sham-operated animals. Overall, fever involves similar central mediators in cycling females and males but only morphine induced fever in OVX females. Importantly, RANK/RANKL participates in LPS-induced fever in OVX females, as in males but not in cycling females.


Assuntos
Citocinas/metabolismo , Febre/etiologia , Hipotálamo/imunologia , Hipotálamo/metabolismo , Lipopolissacarídeos/toxicidade , Ovariectomia/efeitos adversos , Analgésicos Opioides/metabolismo , Animais , Hormônio Liberador da Corticotropina/metabolismo , Endotelina-1/metabolismo , Feminino , Febre/metabolismo , Febre/patologia , Hipotálamo/efeitos dos fármacos , Prostaglandinas/metabolismo , Ligante RANK/metabolismo , Ratos , Ratos Wistar , Substância P/metabolismo
7.
Clin Hemorheol Microcirc ; 75(2): 233-241, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32116239

RESUMO

Roles of nitric oxide (NO) and endothelin-1 (ET-1) in the local regulation of blood flow under physiological conditions are important and well known, while data on their effects and interactions in conditions of hyperbaric hyperoxia is still insufficient. This was a prospective observational study which included patients who underwent hyperbaric oxygen therapy (HBOT) in accordance with existing therapeutic protocol for peripherial arterial disease (PAD) during time period of six months, between january and july of 2016. Clinical stage of PAD according to Fontain was taken into account, as well as risk factors, demographic, anthropometric and clinical characteristics of studied patients. The study included 64 patients with a mean age (±Sd) 60.2±12.7 years, of whom 28 were female. Patients' NO serum levels in all observed categories before and after HBOT were not signifficantly different, except for stage II PAD (NObefore HBOT 21.9±9.6 vs. NOafter HBOT 26.2±12.1 (p = 0.04)). On the contrary, in all studied patients ET-1 level increased signifficantly after HBOT (ET-1before HBOT 4.2±11.6 vs. ET-1after 18.3±21.0 (p < 0.001)). Treatment of PAD using HBOT leads to the predominance of vasoconstrictor effects probably caused by elevation of serum ET-1 concentrations, while other factors such as exposure time to hyperbaric conditions, activation of antioxidant molecules, and the influx of other interfering substances must be considered in interpreting the effects of NO molecules.


Assuntos
Endotelina-1/metabolismo , Oxigenação Hiperbárica/métodos , Óxido Nítrico/metabolismo , Doenças Vasculares/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Doenças Vasculares/sangue
8.
Pregnancy Hypertens ; 20: 83-91, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32199147

RESUMO

OBJECTIVES: There is avid interest in pravastatin as a therapeutic intervention for pre-eclampsia, however little is known on statin action on endothelial dysfunction. This study aimed to evaluate the ability of pravastatin, simvastatin and rosuvastatin to reduce pre-eclampsia-associated markers of endothelial dysfunction in human endothelial cells. STUDY DESIGN: Primary human umbilical vein endothelial cells (HUVECs) and uterine microvascular cells (UtMVs) were isolated and treated with 0.2, 2, 20 and 200 µM pravastatin, simvastatin and rosuvastatin for 24 h, either with or without pre-treatment with TNF-α to induce endothelial dysfunction. MAIN OUTCOME MEASURES: Cell viability (MTS) assays were performed and cells were visually inspected. Expression of endothelial dysfunction markers, endothelin-1 (ET-1) and vascular cell adhesion molecule-1 (VCAM-1) were assessed by qPCR (n=3). Intracellular VCAM-1 protein was examined by Western Blotting (n=5). ET-1 and soluble fms-like tyrosine kinase-1 (sFLT-1) protein secretion was assessed by ELISA in HUVEC conditioned media (n=3). RESULTS: High doses of simvastatin and rosuvastatin significantly compromised HUVEC survival. 200 µM simvastatin significantly reduced UtMV survival. Abnormal cell structure was observed with these doses and thus were excluded from further analysis. The statins did not mitigate TNF-α induced ET-1 or VCAM-1 expression in either HUVECs or UtMVs, nor VCAM-1 protein expression in HUVECs. 0.2 µM pravastatin and simvastatin significantly reduced ET-1 and sFLT-1 protein secretion. CONCLUSIONS: Pravastatin significantly reduced secretion of both ET-1 and sFLT-1, key mediators of endothelial dysfunction. Importantly, pravastatin had no toxic effects, in contrast to rosuvastatin and simvastatin. This further supports selection of pravastatin for clinical applications to combat pre-eclampsia.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Pravastatina/farmacologia , Pré-Eclâmpsia/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Endotelina-1/genética , Endotelina-1/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Pravastatina/toxicidade , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Gravidez , Rosuvastatina Cálcica/farmacologia , Sinvastatina/farmacologia , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
9.
Sci Rep ; 10(1): 3394, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32098974

RESUMO

Although considerable research highlights the interactions between obstructive sleep apnea-hypopnea syndrome (OSAHS) and cardiovascular diseases, the effect of mandibular advancement device (MAD) treatment on cardiovascular complications in OSAHS patients remains unclear. We evaluated the effect of OSAHS treatment with MADs on the myocardium. All methods in this study were in accordance with relevant guidelines and regulations of the medical ethics committee in Hospital of Stomatology, Hebei Medical University approved the work. Thirty New Zealand rabbits were randomized into three groups: the control group, Group OSAHS, and Group MAD. Hydrophilic polyacrylamide gel was injected into the soft palate of the rabbits to induce OSAHS. In Group MAD, a MAD was positioned after OSAHS induction. All animals were induced to sleep in a supine position for 4-6 h/day for 8 weeks. Echocardiography was used to determine the structure and function of the heart. The histological changes were detected by optical microscopy and transmission electron microscopy (TEM). The levels of ET-1(endothelin-1) and Ang II (Angiotensin II) in the plasma were measured by an enzyme-linked immunosorbent assay (ELISA). The expression of ET-1 mRNA in heart tissue was detected by RT-PCR. Histological abnormalities, left ventricular hypertrophy, and left ventricular dysfunctions were demonstrated in Group OSAHS, and the abnormities were rescued with MAD treatment. Higher levels of plasma ET-1 and Ang II and elevated expression of ET-1 mRNA in cardiac tissue were detected in Group OSAHS compared with Group MAD and the control group. The blood oxygen saturation was negatively correlated with the levels of ET-1 and Ang II. OSAHS-induced elevated levels of ET-1 and Ang II may be attributed to myocardial structural abnormalities and dysfunction. Early treatment of MADs may play an important role in preventing myocardial damage in OSAHS rabbit model.


Assuntos
Placas Oclusais , Apneia Obstrutiva do Sono/terapia , Resinas Acrílicas/toxicidade , Angiotensina II/sangue , Animais , Citocinas/metabolismo , Ecocardiografia , Endotelina-1/sangue , Endotelina-1/genética , Endotelina-1/metabolismo , Ensaio de Imunoadsorção Enzimática , Coração/fisiopatologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Polissonografia , RNA Mensageiro/metabolismo , Coelhos , Apneia Obstrutiva do Sono/induzido quimicamente , Disfunção Ventricular Esquerda/patologia
10.
Sci Rep ; 10(1): 1652, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015361

RESUMO

Endothelin 1 (ET-1) has been shown to have a key role in homeostasis and function of endothelium and maybe fundamental in the relationship between coronary heart disease (CHD) and periodontitis. In this trial, we assessed the influence on serum and salivary ET-1 levels of gingival health, CHD, periodontitis, or a combination of periodontitis-CHD. Clinical and periodontal parameters, were collected from periodontitis patients (n = 34), CHD patients (n = 34), periodontitis + CHD patients (n = 34), and from healthy patients (n = 34) together with saliva and serum samples. The median concentrations of salivary and serum ET-1 were significantly higher in the CHD patients [serum: 1.4(1.1-1.6) pg/ml; saliva 1.2 (0.9-1.6) µmol/g, p < 0.01] and in the periodontitis + CHD patients [serum: 1.7 (1.2-21.8) pg/ml; salivary 1.4(1-1.6) µmol/g, p < 0.001] respect to periodontitis and control patients. Through a univariate regression analysis, c-reactive protein (CRP) and CHD (both p < 0.001) and periodontitis (p = 0.029) were statistically correlated with ET-1 in serum. The multivariate regression analysis demonstrated that only CRP was the statistically predictor of ET-1 in serum(p < 0.001). The multivariate regression analysis in saliva demonstrated that, regarding ET-1 levels the only predictor were CRP (p < 0.001) and total cholesterol (p = 0.042). The present study evidenced that subjects with CHD and periodontitis plus CHD had higher serum and salivary levels of ET-1 compared to subjects with periodontitis and healthy controls. Moreover, only CRP remained a major predictor of increased ET-1 concentrations in both serum and saliva.


Assuntos
Endotelina-1/sangue , Endotelina-1/metabolismo , Periodontite/sangue , Periodontite/metabolismo , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Doença das Coronárias/sangue , Doença das Coronárias/complicações , Doença das Coronárias/metabolismo , Feminino , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Periodontite/complicações , Saliva/metabolismo
11.
Life Sci ; 247: 117429, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32061670

RESUMO

AIMS: Hypercholesterolemia is a hazard for increasing susceptibility of the heart to myocardial infarction (MI) by inducing platelet hyperaggregability. Clopidogrel and prasugrel have documented cardioprotective effects in clinical studies. Herein, we investigated whether clopidogrel and prasugrel could protect against isoproterenol-induced acute MI (A-MI) under hypercholesterolemic conditions in rats. MAIN METHODS: Dietary hypercholesterolemic rats were subjected to acute doses of isoproterenol. Serum lipids, inflammatory markers, aortic endothelin1 and endothelial nitric oxide synthase (eNOS) mRNAs expression and immunexpression of BCL2 were determined. KEY FINDINGS: Hypercholesterolemic rats showed infiltration of inflammatory cells and reduction in aortic wall thickness, deposition of fibrous tissue between cardiac muscle fibers. Protective doses of prasugrel or clopidogrel for 28 days before A-MI increased survival, amended the ECG parameters -including ST segment elevation- and improved the histopathological picture in hypercholesterolemic rats. This was coupled with reductions in platelet aggregation, creatine kinase-MB activity, endothelin 1, systemic inflammation and cardiac lipid peroxidation and increment in aortic eNOS expression. Clopidogrel and prasugrel groups showed enhanced BCL2 expression in cardiac fibers and aortic wall. SIGNIFICANCE: Prasugrel and clopidogrel protected against A-MI via anti-aggregatory and anti-inflammatory effects. These results add to the value of these drugs in correcting cardiovascular dysfunction in patients vulnerable to A-MI after confirmation by appropriate human studies.


Assuntos
Clopidogrel/uso terapêutico , Hipercolesterolemia/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Animais , Sistema Cardiovascular/efeitos dos fármacos , Creatina Quinase Forma MB/metabolismo , Endotelina-1/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Modelos Animais , Mortalidade , Óxido Nítrico Sintase Tipo III/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Resultado do Tratamento
12.
J Food Sci ; 85(3): 576-581, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32078759

RESUMO

Elevated free fatty acids may impair insulin-mediated signaling to eNOS that contributes to the pathophysiology of endothelial dysfunction. Previous studies have indicated the protective effect of ginseng and the regulatory potential of phenolic acid components from other plants on endothelial function. Therefore, this study investigated the protective effects of phenolic acid extract from ginseng (PG2) on endothelial cells against palmitate-induced damage. We found that PG2 increases cell viability, inhibits the palmitate-induced intracellular accumulation of lipids, and the overexpression of endothelin-1 (ET-1) through enhancing the phosphorylation of the phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase (PI3K/Akt/eNOS) signaling pathway. The results of this study may be valuable for the development of PG2 to combat the endothelial cell damage caused by hyperlipidemia. PRACTICAL APPLICATION: We proved that phenolic acid extract from ginseng has a protective effect on free fatty acid-induced endothelial dysfunction in vitro. This study provides experimental data for the application of ginseng-derived phenolic acids in treating cardiovascular disease.


Assuntos
Células Endoteliais/efeitos dos fármacos , Hidroxibenzoatos/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Panax/química , Fosfatidilinositol 3-Quinase/metabolismo , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/enzimologia , Endotelina-1/metabolismo , Humanos , Insulina/metabolismo , Palmitatos/toxicidade , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
13.
Oxid Med Cell Longev ; 2020: 9367673, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089786

RESUMO

The regulatory mechanisms for proliferation and migration of vascular smooth muscle cells have not yet been clear. The present study was designed to investigate whether and how endothelin-1 (ET-1) impacted the generation of endogenous sulfur dioxide (SO2) in rat vascular smooth muscle cell (VSMC) proliferation and migration. Primary VSMCs and purified aspartate aminotransferase (AAT) protein were used in this study. We found that in the presence of ET-1, the expression of PCNA and Ki-67 was upregulated and the migration of VSMCs was promoted, while the AAT activity and SO2 levels in VSMCs were reduced without any changes in AAT1 and AAT2 expression. SO2 supplementation successfully prevented the ET-1-facilitated expression of PCNA and Ki-67 and the migration of VSMCs. Interestingly, ET-1 significantly increased reactive oxygen species (ROS) production in association with SO2/AAT pathway downregulation in VSMCs compared with controls, while the ROS scavenger N-acetyl-L-cysteine (NAC) and the antioxidant glutathione (GSH) significantly abolished the ET-1-stimulated downregulation of the SO2/AAT pathway. Moreover, the AAT activity was reduced in purified protein after the treatment for 2 h. However, NAC and GSH blocked the hydrogen peroxide-induced AAT activity reduction. In conclusion, our results suggest that ET-1 results in the downregulation of the endogenous SO2/AAT pathway via ROS generation to enhance the proliferation and migration of VSMCs.


Assuntos
Aspartato Aminotransferases/metabolismo , Endotelina-1/metabolismo , Músculo Liso Vascular/metabolismo , Dióxido de Enxofre/metabolismo , Animais , Movimento Celular , Proliferação de Células , Regulação para Baixo , Humanos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio
14.
J Cardiovasc Pharmacol ; 75(4): 292-298, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31895874

RESUMO

Healthy vascular endothelial cells regulate vascular tone and permeability, prevent vessel wall inflammation, enhance thromboresistance, and contribute to general vascular health. Furthermore, they perform important functions including the production of vasoactive substances such as nitric oxide (NO) and endothelium-derived hyperpolarizing factors, as well as the regulation of smooth muscle cell functions. Conversely, vascular endothelial dysfunction leads to atherosclerosis, thereby enhancing the risk of stroke, myocardial infarction, and other cardiovascular diseases (CVDs). Observational studies and randomized trials showed that green tea intake was inversely related to CVD risk. Furthermore, evidence indicates that epigallocatechin gallate (EGCG) found in green tea might exert a preventive effect against CVDs. EGCG acts as an antioxidant, inducing NO release and reducing endothelin-1 production in endothelial cells. EGCG enhances the bioavailability of normal NO by reducing levels of the endogenous NO inhibitor asymmetric dimethylarginine. Furthermore, it inhibits the enhanced expression of adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 and attenuates monocyte adhesion. In addition, EGCG prevents enhanced oxidative stress through the Nrf2/HO-1 pathway. These effects indicate that it might prevent the production of reactive oxygen species, inhibit inflammation, and reduce endothelial cell apoptosis during the initial stages of atherosclerosis. The current review summarizes recent research in this area and discusses novel findings regarding the protective effect of EGCG on endothelial dysfunction and CVDs in general.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Catequina/análogos & derivados , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Animais , Anti-Inflamatórios/efeitos adversos , Antioxidantes/efeitos adversos , Apoptose/efeitos dos fármacos , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Catequina/efeitos adversos , Catequina/uso terapêutico , Moléculas de Adesão Celular/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotelina-1/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Humanos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos
15.
J Am Soc Nephrol ; 31(3): 469-482, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31988269

RESUMO

Retrospective analyses and single-center prospective studies identify chronic metabolic acidosis as an independent and modifiable risk factor for progression of CKD. In patients with CKD, untreated chronic metabolic acidosis often leads to an accelerated reduction in GFR. Mechanisms responsible for this reduction include adaptive responses that increase acid excretion but lead to a decline in kidney function. Metabolic acidosis in CKD stimulates production of intrakidney paracrine hormones including angiotensin II, aldosterone, and endothelin-1 (ET-1) that mediate the immediate benefit of increased kidney acid excretion, but their chronic upregulation promotes inflammation and fibrosis. Chronic metabolic acidosis also stimulates ammoniagenesis that increases acid excretion but also leads to ammonia-induced complement activation and deposition of C3 and C5b-9 that can cause tubule-interstitial damage, further worsening disease progression. These effects, along with acid accumulation in kidney tissue, combine to accelerate progression of kidney disease. Treatment of chronic metabolic acidosis attenuates these adaptive responses; reduces levels of angiotensin II, aldosterone, and ET-1; reduces ammoniagenesis; and diminishes inflammation and fibrosis that may lead to slowing of CKD progression.


Assuntos
Acidose/complicações , Aldosterona/metabolismo , Angiotensina II/metabolismo , Progressão da Doença , Endotelina-1/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Equilíbrio Ácido-Base/efeitos dos fármacos , Equilíbrio Ácido-Base/fisiologia , Acidose/diagnóstico , Acidose/tratamento farmacológico , Adaptação Fisiológica/fisiologia , Biomarcadores/sangue , Feminino , Seguimentos , Taxa de Filtração Glomerular/fisiologia , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/fisiopatologia , Masculino , Estudos Prospectivos , Insuficiência Renal Crônica/etiologia , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
16.
Molecules ; 25(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31906332

RESUMO

Astragalin, isolated from flowers of Rosa chinensis Jacq., is a kind of flavonoid, with anti-inflammatory, antioxidant, antiviral, analgesic, antibacterial, antiallergic, and antihepatotoxic effects. However, no studieson the procoagulant effect of astragalin have been reported. This study aimed to investigate the procoagulant activity of astragalin and its mechanism. Its procoagulant effect was investigated by activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT), and fibrinogen (FIB) in vitro, and a rat model established by heparin sodium was used to evaluate the mechanism for the procoagulant effect in vivo. The results showed that astragalin had good procoagulant effects compared with the control group in vitro. Compared with the model group in vivo, astragalin could shorten the coagulation time and significantly increase the number of platelets. Meanwhile, astragalin could significantly reduce the effectual time of PT and APTT and increase the content of FIB. The contents of 6-keto-PGF1α and eNOS significantly decreased. Astragalin could increase whole blood viscosity (WBV), plasma viscosity (PV), erythrocyte sedimentation rate (ESR) and packedcell volume (PCV). All of the above revealed that astragalin had good procoagulant effects by promoting the intrinsic and extrinsic coagulation system.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Fibrinogênio/metabolismo , Quempferóis/farmacologia , Agregação Plaquetária/efeitos dos fármacos , 6-Cetoprostaglandina F1 alfa/metabolismo , Animais , Testes de Coagulação Sanguínea , Sedimentação Sanguínea/efeitos dos fármacos , Viscosidade Sanguínea/efeitos dos fármacos , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Endotelina-1/metabolismo , Feminino , Flavonoides/metabolismo , Flavonoides/farmacologia , Quempferóis/química , Quempferóis/isolamento & purificação , Quempferóis/metabolismo , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Coelhos , Ratos , Ratos Sprague-Dawley , Rosaceae/química , Tempo de Trombina , Tromboxano B2/metabolismo
17.
Biomed Pharmacother ; 123: 109758, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31864211

RESUMO

Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a key role in atherosclerosis. Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis. HHcy induces phenotypic switching of VSMCs, but the mechanism is unclear. Endothelin-1 (ET-1) promotes proliferation and migration of VSMCs by inducing phenotypic switching during atherosclerosis. This review examined recent findings on the relationship between HHcy or the ET-1 system (including ET-1 and its receptors) and phenotypic switching of VSMCs as well as the molecular mechanism of HHcy-regulated ET-1 signaling. In particular, we focused on the potential mechanisms and pharmacological targets of phenotypic switching of VSMCs regulated by HHcy through ET-1 signaling.


Assuntos
Endotelina-1/metabolismo , Hiper-Homocisteinemia/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fenótipo , Animais , Aterosclerose/metabolismo , Proliferação de Células , Humanos , Fosforilação , Transdução de Sinais
18.
J BUON ; 24(5): 1913-1919, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31786855

RESUMO

PURPOSE: The endothelin system is involved in the evolution of multiple malignancies, participating in cancer cell proliferation, tumor invasion and angiogenesis. Our purpose was to simultaneously assess endothelin expression in the systemic circulation of patients with lobular neoplasia (LN) of the breast and to investigate its correlation with vascular endothelial growth factor (VEGF) specimen expression levels as well as clinicopathologic findings. METHODS: This was a retrospective analysis of prospectively collected data regarding 60 women examined in a single breast unit. Thirty of these women underwent stereotactic biopsy and were diagnosed with LN and the remaining 30 were healthy controls. Circulating levels of endothelin (ET)-1 and Big ET-1 were measured using ELISA, while tissue expression of ET-1 and VEGF in biopsy specimens were assessed using qualitative immunohistochemical staining. RESULTS: The plasma levels of Big ET-1 were significantly increased in patients with LN compared to healthy controls. There was no significant difference in the plasma levels of ET-1 between the patient groups. In patients with LN, plasma expression of ET-1 and Big ET-1 did not correlate with ET-1 or VEGF tissue expression status, neither existed a relationship between tissue expressions of ET-1 and VEGF. CONCLUSIONS: Our results imply that Big ET-1 is a potential biomarker for LN. Further investigation of the endothelin system role in LN seems a promising research field.


Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/metabolismo , Mama/metabolismo , Endotelina-1/sangue , Endotelina-1/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Neovascularização Patológica/sangue , Neovascularização Patológica/metabolismo , Lesões Pré-Cancerosas/sangue , Lesões Pré-Cancerosas/metabolismo , Estudos Retrospectivos
19.
J. bras. nefrol ; 41(4): 451-461, Out.-Dec. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1056616

RESUMO

ABSTRACT Hypertension and Diabetes mellitus are the two main causes of chronic kidney disease that culminate in the final stage of kidney disease. Since these two risk factors are common and can overlap, new approaches to prevent or treat them are needed. Macitentan (MAC) is a new non-selective antagonist of the endothelin-1 (ET-1) receptor. This study aimed to evaluate the effect of chronic blockade of ET-1 receptor with MAC on the alteration of renal function observed in hypertensive and hyperglycemic animals. Genetically hypertensive rats were divided into control hypertensive (HT-CTL) group, hypertensive and hyperglycemic (HT+DIAB) group, and hypertensive and hyperglycemic group that received 25 mg/kg macitentan (HT-DIAB+MAC25) via gavage for 60 days. Kidney function and parameters associated with oxidative and nitrosative stress were evaluated. Immunohistochemistry for neutrophil gelatinase-associated lipocalin (NGAL), ET-1, and catalase in the renal cortex was performed. The HT+DIAB group showed a decrease in kidney function and an increase in NGAL expression in the renal cortex, as well as an increase in oxidative stress. MAC treatment was associated with attenuated ET-1 and NGAL production and increases in antioxidant defense (catalase expression) and nitric oxide production. In addition, MAC prevented an increase in oxidant injury (as measured by urinary hydroperoxide and lipid peroxidation), thus improving renal function. Our results suggest that the antioxidant effect of the ET-1 receptor antagonist MAC is involved in the improvement of kidney function observed in hypertensive and hyperglycemic rats.


RESUMO Hipertensão e Diabetes Mellitus figuram como as duas principais causas de doença renal crônica que culmina em doença renal terminal. Uma vez que os dois fatores de risco são comuns e podem se sobrepor, novas abordagens preventivas e terapêuticas se fazem necessárias. O macitentan (MAC) é um novo antagonista não-seletivo dos receptores da endotelina-1 (ET-1). O presente estudo teve como objetivo avaliar os efeitos do bloqueio crônico dos receptores da ET-1 com MAC sobre a alteração da função renal em animais hipertensos e hiperglicêmicos. Ratos geneticamente hipertensos foram divididos em grupos com animais hipertensos de controle (HT-CTL), hipertensos e hiperglicêmicos (HT+DIAB) e hipertensos e hiperglicêmicos tratados com 25 mg/kg de macitentan (HT-DIAB+MAC25) via gavagem por 60 dias. Foram avaliados função renal e parâmetros associados ao estresse oxidativo e nitrosativo. Exames de imunoistoquímica foram realizados para lipocalina associada à gelatinase neutrofílica (NGAL), ET-1 e catalase no córtex renal. O grupo HT+DIAB exibiu diminuição da função renal e aumento na expressão de NGAL no córtex renal, bem como estresse oxidativo aumentado. O tratamento com MAC foi associado a atenuação da produção de ET-1 e NGAL e maior ativação das defesas antioxidantes (expressão de catalase) e elevação da produção de óxido nítrico. Além disso, o MAC evitou exacerbação da lesão oxidante (medida por hidroperóxidos urinários e peroxidação lipídica), melhorando assim a função renal. Nossos resultados sugerem que o efeito antioxidante do antagonista dos receptores da ET-1 MAC esteja imbricado no aprimoramento da função renal observada em ratos hipertensos e hiperglicêmicos.


Assuntos
Humanos , Animais , Masculino , Hiperglicemia/complicações , Rim/efeitos dos fármacos , Antioxidantes/farmacologia , Ratos/genética , Fatores de Risco , Endotelina-1/metabolismo , Administração Intravenosa , Antagonistas dos Receptores de Endotelina/administração & dosagem , Antagonistas dos Receptores de Endotelina/uso terapêutico , Hiperglicemia/induzido quimicamente , Hipertensão/complicações , Hipertensão/fisiopatologia , Rim/fisiopatologia , Rim/lesões , Antibióticos Antineoplásicos/administração & dosagem
20.
Int J Mol Sci ; 20(23)2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31766450

RESUMO

Ventricular arrhythmia (VA) is a major component of sudden cardiac death (SCD). To investigate the expression of brain natriuretic peptide (BNP), endothelin-1 (ET-1), and transforming growth factor-beta 1 (TGF-ß1) during VA, we established a rat model of VA induced by BaCl2 solution through a microinjector pump. PD142893 (ET-1 receptor blocker) and SB431542 (TGF-ß1 receptor type I blocker) were used to explore the effect of ET-1 and TGF-ß1 on BNP expression in the myocardium after VA. BNP, ET-1, and TGF-ß1 in rat myocardium were assayed by western blot and immunohistochemical staining for proteins, and real-time quantitative polymerase chain reaction for mRNAs. We found increased expression of BNP and ET-1 in rat myocardium that was associated with the duration of VA. However, TGF-ß1 protein expression remained unchanged. Such early increases in BNP and ET-1 may be attributed to fatal arrhythmias associated with SCD, suggesting these may be novel biomarkers of this disease. After intraperitoneal injection of PD142893 and SB431542, respectively, BNP was downregulated in the myocardium of the left ventricle; however, this was abrogated by co-application of the two inhibitors. These results suggested that both ET-1 and TGF-ß1, by specifically binding to their receptors, might be involved in the myocardial synthesis of BNP during VA in vivo.


Assuntos
Arritmias Cardíacas/genética , Endotelina-1/genética , Miocárdio/metabolismo , Peptídeo Natriurético Encefálico/genética , Fator de Crescimento Transformador beta1/genética , Animais , Arritmias Cardíacas/complicações , Arritmias Cardíacas/metabolismo , Benzamidas/farmacologia , Morte Súbita Cardíaca/etiologia , Dioxóis/farmacologia , Antagonistas dos Receptores de Endotelina/farmacologia , Endotelina-1/metabolismo , Expressão Gênica , Masculino , Miocárdio/patologia , Peptídeo Natriurético Encefálico/metabolismo , Oligopeptídeos/farmacologia , Ratos Sprague-Dawley , Receptores de Endotelina/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
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