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1.
Am J Physiol Endocrinol Metab ; 317(3): E548-E558, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31310581

RESUMO

Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory peptide that is upregulated in obesity. Herein, we tested the hypothesis that ET-1 signaling promotes visceral adipose tissue (AT) inflammation and disrupts glucose homeostasis. We also tested if reduced ET-1 is a required mechanism by which exercise ameliorates AT inflammation and improves glycemic control in obesity. We found that 1) diet-induced obesity, AT inflammation, and glycemic dysregulation were not accompanied by significantly increased levels of ET-1 in AT or circulation in wild-type mice and that endothelial overexpression of ET-1 and consequently increased ET-1 levels did not cause AT inflammation yet impaired glucose tolerance; 2) reduced AT inflammation and improved glucose tolerance with voluntary wheel running was not associated with decreased levels of ET-1 in AT or circulation in obese mice nor did endothelial overexpression of ET-1 impede such exercise-induced metabolic adaptations; 3) chronic pharmacological blockade of ET-1 receptors did not suppress AT inflammation in obese mice but improved glucose tolerance; and 4) in a cohort of human subjects with a wide range of body mass indexes, ET-1 levels in AT, or circulation were not correlated with markers of inflammation in AT. In aggregate, we conclude that ET-1 signaling is not implicated in the development of visceral AT inflammation but promotes glucose intolerance, thus representing an important therapeutic target for glycemic dysregulation in conditions characterized by hyperendothelinemia. Furthermore, we show that the salutary effects of exercise on AT and systemic metabolic function are not contingent on the suppression of ET-1 signaling.


Assuntos
Endotelina-1/metabolismo , Intolerância à Glucose/metabolismo , Inflamação/patologia , Gordura Intra-Abdominal/patologia , Condicionamento Físico Animal/fisiologia , Animais , Índice de Massa Corporal , Endotelina-1/antagonistas & inibidores , Endotelina-1/genética , Exercício Físico/fisiologia , Feminino , Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Obesidade/patologia , Corrida
2.
Clin Nephrol ; 91(6): 370-379, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30990410

RESUMO

AIMS: Endothelin-1 (ET-1) is associated with the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD) via cyst progression. Elevated concentrations of ET-1 in ADPKD correlate with many phenotypic changes in the kidney such as renal cyst development, interstitial fibrosis, and glomerulosclerosis. In addition, an imbalance between renal ETA and ETB receptors possibly leads to more severe disease progression. The objective of this review is to determine whether evaluating the efficacy of these drugs in treatment of cystic kidney disease may be a worthwhile aim, as determined by results from animal and human models. MATERIALS AND METHODS: PubMed/Medline, Embase, and Google Scholar databases were searched using the key words "endothelin, endothelin-1 antagonists, and autosomal dominant polycystic kidney disease". All animal and human studies describing the effects of endothelin and endothelin-1 antagonists in ADPKD subjects were included in the review. RESULTS: Urinary ET-1 concentrations could serve as a noninvasive surrogate biomarker for kidney ET-1 levels, as it is inversely associated with eGFR, independent of age, sex, and blood pressure. Elevated urinary excretion of ET-1 may be a biomarker for early renal injury. Antagonization of ET-1 may hopefully be a novel therapy for slowing progression of kidney damage in ADPKD. CONCLUSION: Based on the literature reviewed in this manuscript, it is proposed that further research evaluating the efficacy of endothelin antagonists in treatment of cystic kidney disease is warranted. More human studies need to be performed with larger sample sizes. Therefore, the recommendation for treatment is inconclusive at this time.
.


Assuntos
Endotelina-1/antagonistas & inibidores , Endotelina-1/urina , Rim Policístico Autossômico Dominante/tratamento farmacológico , Animais , Biomarcadores/urina , Progressão da Doença , Taxa de Filtração Glomerular , Humanos , Rim Policístico Autossômico Dominante/fisiopatologia
3.
Biomed Pharmacother ; 110: 431-439, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30530045

RESUMO

The SUR2B/Kir6.1 channel openers iptakalim and natakalim reverse cardiac remodeling and ameliorate endothelial dysfunction by re-establishing the balance between the nitric oxide and endothelin systems. In this study, we investigated the microRNAs (miRs) involved in the molecular mechanisms of SUR2B/Kir6.1 channel opening in chronic heart failure. Both iptakalim and natakalim significantly upregulated the expression of miR-1-3p, suggesting that this miR is closely associated with the therapeutic effects against chronic heart failure. Bioinformatic analysis showed that many of the 183 target genes of miR-1-3p are involved in cardiovascular diseases, suggesting that miR-1-3p plays a vital role in such diseases and vascular remodeling. Target gene prediction showed that miR-1-3p combines with the 3' untranslated region (UTR) of endothelin-1 (ET-1) mRNA. Iptakalim and natakalim upregulated miR-1-3p expression and downregulated ET-1 mRNA expression in vitro. The dual luciferase assay confirmed that there is a complementary binding sequence between miR-1-3p and the 3' UTR 158-165 sequence of ET-1 mRNA. To verify the effect of miR-1-3p on ET-1, lentiviral vectors overexpressing or inhibiting miR-1-3p were constructed for the transduction of rat primary cardiac microvascular endothelial cells. The results showed that natakalim enhanced the miR-1-3p level. miR-1-3p overexpression downregulated the expression of ET-1, whereas miR-1-3p inhibition had the opposite effect. Therefore, we verified that SUR2B/Kir6.1 channel openers could correct endothelial imbalance and ameliorate chronic heart failure through the miR-1-3p/ET-1 pathway in endothelial cells. Our study provides comprehensive insights into the molecular mechanisms behind the SUR2B/Kir6.1 channel's activity against chronic heart failure.


Assuntos
Endotelina-1/metabolismo , Endotélio Vascular/metabolismo , Insuficiência Cardíaca/metabolismo , Canais KATP/metabolismo , MicroRNAs/metabolismo , Receptores Sulfonilureia/metabolismo , Compostos Alílicos/farmacologia , Compostos Alílicos/uso terapêutico , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Endotelina-1/antagonistas & inibidores , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Células HEK293 , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , Humanos , Canais KATP/agonistas , MicroRNAs/antagonistas & inibidores , Propilaminas/farmacologia , Propilaminas/uso terapêutico , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Receptores Sulfonilureia/agonistas
4.
Phytomedicine ; 51: 205-213, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30466619

RESUMO

BACKGROUND: Magnolol, a major bioactive component extracted from Magnolia officinalis, exerts several beneficial effects, such as anti-inflammatory and anti-hypertensive activities. PURPOSE: In this study, we investigated whether magnolol has a protective effect on pneumonectomy and monocrotaline-induced pulmonary arterial hypertension (PAH) in rats. DESIGN/METHODS: The alterations of right ventricular (RV) hypertrophy, pulmonary vascular remodeling, histopathological parameters, and related gene expression and signaling pathways in lungs by magnolol treatment were studied in the PAH rats. RESULTS: Administration of magnolol greatly ameliorated the characteristic features of PAH, including increased pulmonary arterial pressure, RV hypertrophy, and pulmonary vascular remodeling. Moreover, magnolol inhibited angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II type 1 receptor (AT-1R) cascade, whereas upregulates ACE2 in the lungs of PAH rats. The overexpression of endothelin-1 (ET-1) and ETA receptor occurred in the PAH rats was significantly attenuated by magnolol through inhibition of Akt/ERK1/2/GSK3ß/ß-catenin pathway. Compared with that of untreated PAH rats, higher expression of endothelial nitric oxide synthase, and lower expression of inducible nitric oxide synthase and O2- production in lungs were observed in magnolol-treated PAH rats. CONCLUSION: We demonstrated that treatment with magnolol reduces the development of PAH induced by pneumonectomy and monocrotaline in rats, and suppressing Ang II and ET-1-mediated processes may contribute to its protective effects. These findings suggest that magnolol may be a potential agent for PAH therapy.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Compostos de Bifenilo/farmacologia , Endotelina-1/antagonistas & inibidores , Hipertensão Pulmonar/tratamento farmacológico , Lignanas/farmacologia , Angiotensina II/metabolismo , Animais , Endotelina-1/metabolismo , Hipertensão Pulmonar/induzido quimicamente , Hipertrofia Ventricular Direita , Pulmão/fisiopatologia , Masculino , Monocrotalina , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonectomia , Artéria Pulmonar/fisiopatologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Remodelação Vascular
5.
J Trauma Acute Care Surg ; 85(4): 725-733, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30086070

RESUMO

BACKGROUND: Hemorrhagic shock-induced changes in vascular reactivity appear organ-specific. In the present study, we examined the hypothesis that vascular reactivity induced by septic shock similarly displays organ-specific differences and is regulated by inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1). METHODS: Endotoxic shock was induced in rabbits by administration of lipopolysaccharide (LPS) (1 mg/kg), and organ specificity of vascular reactivity of superior mesenteric artery (SMA), celiac artery (CA), and left renal artery (LRA) as well as the potential involvement of iNOS and ET-1 examined. RESULTS: Vascular reactivity of SMA, CA, and LRA was increased at the early stages and decreased at the late stages after LPS administration. Superior mesenteric artery showed the greatest decrease in vascular reactivity in response to norepinephrine (NE) (34.9%) and acetylcholine (Ach; 32.3%), followed by LRA (NE, 33.7%; Ach, 30.5%) and CA (NE, 16.2%), whereas the relaxation reactivity of CA in response to Ach was increased to 159%. The mRNA and protein levels of iNOS and ET-1 in SMA, CA, and LRA were not affected at the early stages of endotoxic shock after LPS administration but significantly increased at the late stages. Expression levels were higher in SMA than CA and LRA and negatively correlated with the decrease in vascular reactivity. The iNOS and ET-1 inhibitors, aminoguanidine (20 mg/kg) and PD-142893 (0.02 mg/kg), respectively, induced significant improvements in vascular reactivity and organ perfusion and stabilized the hemodynamic parameters in rabbits subjected to endotoxic shock. CONCLUSION: Changes in vascular reactivity during endotoxic shock are organ-specific. Differential expression patterns of iNOS and ET-1 in different blood vessels contribute to the organ specificity of vascular reactivity. LEVEL OF EVIDENCE: Therapeutic study, level II.


Assuntos
Endotelina-1/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Choque Séptico/fisiopatologia , Vasoconstrição , Vasodilatação , Acetilcolina/farmacologia , Animais , Artéria Celíaca/metabolismo , Modelos Animais de Doenças , Antagonistas do Receptor de Endotelina A/farmacologia , Endotelina-1/antagonistas & inibidores , Endotelina-1/genética , Inibidores Enzimáticos/farmacologia , Feminino , Guanidinas/farmacologia , Ácido Láctico/sangue , Lipopolissacarídeos , Masculino , Artéria Mesentérica Superior/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Norepinefrina/farmacologia , Oligopeptídeos/farmacologia , RNA Mensageiro/metabolismo , Coelhos , Artéria Renal/metabolismo , Choque Séptico/induzido quimicamente , Choque Séptico/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
6.
Physiol Res ; 67(Suppl 1): S55-S67, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29947528

RESUMO

Chronic kidney disease (CKD) is a life-threatening disease arising as a frequent complication of diabetes, obesity and hypertension. Since it is typically undetected for long periods, it often progresses to end-stage renal disease. CKD is characterized by the development of progressive glomerulosclerosis, interstitial fibrosis and tubular atrophy along with a decreased glomerular filtration rate. This is associated with podocyte injury and a progressive rise in proteinuria. As endothelin-1 (ET-1) through the activation of endothelin receptor type A (ET(A)) promotes renal cell injury, inflammation, and fibrosis which finally lead to proteinuria, it is not surprising that ET(A) receptors antagonists have been proven to have beneficial renoprotective effects in both experimental and clinical studies in diabetic and non-diabetic CKD. Unfortunately, fluid retention encountered in large clinical trials in diabetic CKD led to the termination of these studies. Therefore, several advances, including the synthesis of new antagonists with enhanced pharmacological activity, the use of lower doses of ET antagonists, the addition of diuretics, plus simply searching for distinct pathological states to be treated, are promising targets for future experimental studies. In support of these approaches, our group demonstrated in adult subtotally nephrectomized Ren-2 transgenic rats that the addition of a diuretic on top of renin-angiotensin and ET(A) blockade led to a further decrease of proteinuria. This effect was independent of blood pressure which was normalized in all treated groups. Recent data in non-diabetic CKD, therefore, indicate a new potential for ET(A) antagonists, at least under certain pathological conditions.


Assuntos
Diuréticos/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Receptor de Endotelina A/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/prevenção & controle , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Diuréticos/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Endotelina-1/antagonistas & inibidores , Endotelina-1/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia
7.
Physiol Res ; 67(Suppl 1): S69-S81, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29947529

RESUMO

The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. Impaired vasodilator reactivity has been recognized as an early hemodynamic abnormality in obese patients, but also increased vasoconstrictor tone importantly contributes to their vascular damage. In particular, upregulation of the endothelin (ET)-1 system, consistently reported in these patients, might accelerate atherosclerosis and its complication, given the pro-inflammatory and mitogenic properties of ET-1. In recent years, a number of gut hormones, in addition to their role as modulators of food intake, energy balance, glucose and lipid metabolism, and insulin secretion and action, have demonstrated favorable vascular actions. They increase the bioavailability of vasodilator mediators like nitric oxide, but they have also been shown to inhibit the ET-1 system. These features make gut hormones promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant advantages. Therefore, there is real hope that better understanding of the properties of gut-derived substances might provide more effective therapies for the obesity-related cardiometabolic syndrome.


Assuntos
Endotelina-1/metabolismo , Hormônios Gastrointestinais/metabolismo , Obesidade/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/administração & dosagem , Vasoconstritores/metabolismo , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Endotelina-1/agonistas , Endotelina-1/antagonistas & inibidores , Hormônios Gastrointestinais/antagonistas & inibidores , Humanos , Resistência à Insulina/fisiologia , Obesidade/tratamento farmacológico , Hormônios Peptídicos/antagonistas & inibidores , Hormônios Peptídicos/metabolismo , Vasoconstrição/fisiologia
8.
Physiol Res ; 67(Suppl 1): S237-S246, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29947543

RESUMO

Diabetes increases the risk and worsens the progression of cognitive impairment. The hippocampus is an important domain for learning and memory. We previously showed that endothelin-1 (ET-1) reduced diabetes-induced inflammation in hippocampal neurons, suggesting a neuroprotective effect. Given that neurons and endothelial cells within the neurovascular unit depend on each other for proper function, we investigated the effect of ET-1 on brain-derived neurotrophic factor (BDNF) synthesis, a key neurotrophin and prosurvival factor, in neuronal (HT22 hippocampal neurons) and brain microvascular endothelial (BMEC-5i) cells under normal and diabetes-mimicking (high glucose plus palmitate) conditions. Cells were treated with exogenous ET-1 or ET receptor antagonists including ET(B) receptor selective antagonist BQ788 (1 microM) or dual-receptor antagonist bosentan (10 microM). Mature (m)BDNF, proBDNF and caspase-3 levels were measured by Western blotting. Diabetic conditions reduced the prosurvival mBDNF/proBDNF ratio in both HT22 and BMEC-5i cells. Addition of exogenous ET-1 had no effect on the BDNF system in HT22 cells in diabetic conditions. Both HT22 and BMEC-5i cells had an increase in the mBDNF/proBDNF ratio when grown in diabetes-simulating conditions in the presence of endothelin receptor inhibition. These data suggest that blockade of ET-1 may provide neuroprotection to hippocampal cells through the modulation of the BDNF system.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Células Endoteliais/metabolismo , Endotelina-1/metabolismo , Glucose/toxicidade , Neurônios/metabolismo , Palmitatos/toxicidade , Animais , Linhagem Celular Transformada , Células Endoteliais/efeitos dos fármacos , Endotelina-1/antagonistas & inibidores , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Neurônios/efeitos dos fármacos
9.
Lung ; 196(3): 321-327, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29516177

RESUMO

INTRODUCTION: A number of studies indicate that endothelin-1 (ET-1) may act as an inflammatory cell "gatekeeper," by regulating the influx of neutrophils following pulmonary injury. To further examine the role of ET-1 in modulating lung inflammation, hamsters were treated with an endothelin receptor antagonist (ERA), HJP272, either 1 h prior to intratracheal instillation of amiodarone (AM) or 24 h afterwards. METHODS: In both cases, the extent of lung injury and repair was determined by (1) histopathological changes; (2) neutrophil content in bronchoalveolar lavage fluid (BALF); (3) lung collagen content; (4) tumor necrosis factor receptor 1 expression by BALF macrophages; (5) BALF levels of (a) transforming growth factor beta-1, (b) stromal cell-derived factor 1 (commonly referred to as CXCL12), and (c) platelet-derived growth factor BB; (6) alveolar septal cell apoptosis. RESULTS: For each parameter, pretreatment with HJP272 resulted in a significant reduction compared to AM alone, whereas post-treatment was either ineffective or produced only a marginally significant change, suggesting that the course of lung inflammation and repair is programmed at a very early stage. CONCLUSIONS: This finding may explain why ERAs are not an effective treatment for human pulmonary fibrosis. Nevertheless, they may be useful as an adjunct to therapeutic regimens involving drugs that have fibrogenic potential.


Assuntos
Amiodarona/toxicidade , Antagonistas dos Receptores de Endotelina/farmacologia , Endotelina-1/antagonistas & inibidores , Hidroxiquinolinas/farmacologia , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Vasodilatadores/toxicidade , Animais , Apoptose/efeitos dos fármacos , Becaplermina/efeitos dos fármacos , Becaplermina/metabolismo , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Quimiocina CXCL12/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Colágeno/efeitos dos fármacos , Colágeno/metabolismo , Feminino , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Mesocricetus , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Receptores Tipo I de Fatores de Necrose Tumoral/efeitos dos fármacos , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo
10.
Sci Rep ; 8(1): 3076, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29449619

RESUMO

Arterial stiffness may contribute to the pathogenesis of hypertension. The goal of this study is to elucidate the role of Endothelin-1 (ET-1) in aortic stiffening-induced hypertension through ETA receptor activation. An increase in aortic stiffness was created by use of a non-constrictive restraint, NCR on the abdominal aortic surface. A group of rats underwent aortic NCR or sham operation for 12 weeks and were then treated with ETA receptor antagonist BQ-123 for 3 weeks. We found that 12 weeks of aortic NCR significantly increased pulse and mean pressure and altered peripheral flow pattern, accompanied by an increased serum ET-1 level (p < 0.05). The increase in aortic stiffness (evidenced by an elevated pulse wave velocity) caused hypertrophic structural remodeling and decreased arterial compliance, along with an impaired endothelial function in peripheral small arteries. BQ-123 treatment only partially attenuated peripheral arterial hypertrophy and restored arterial compliance, but completely recovered endothelium function, and consequently restored local flow and lowered blood pressure. Our findings underscore the hemodynamic coupling between aortic stiffening and peripheral arterial vessels and flow dynamics through an ETA-dependent mechanism. ETA receptor blockade may have therapeutic potential for improving peripheral vessel structure and function in the treatment of aortic stiffness-induced hypertension.


Assuntos
Endotelina-1/metabolismo , Hipertensão/metabolismo , Rigidez Vascular/fisiologia , Animais , Aorta/efeitos dos fármacos , Artérias/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Endotelina-1/antagonistas & inibidores , Endotelina-1/fisiologia , Feminino , Hemodinâmica , Hipertensão/fisiopatologia , Masculino , Análise de Onda de Pulso , Ratos , Ratos Wistar
11.
Klin Monbl Augenheilkd ; 235(2): 140-145, 2018 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-29448283

RESUMO

This review article is focused on the various facets of possible endothelin's role in glaucoma; involvement of endothelin in other ocular, in particular vascular, diseases is not specifically discussed. Endothelin is an ubiquitous molecule that occurs in practically all ocular tissues. Its primary physiological function is regulation of the blood vessel diameter and hence regulation of the blood supply in tissues. It is secreted locally, and exerts its effect also predominantly locally. This limits the value of venous blood sampling for estimation of the endothelin function in a particular patient, or in study cohorts as well. Endothelin is involved in the regulation of intraocular pressure, in the regulation of blood flow and in activation of retinal and optic nerve head astrocytes. All these functions are of high importance when it comes to pathogenesis of glaucoma. Possible future directions for glaucoma treatment should encompass pharmacological antagonism to endothelin, an avenue which is at present hindered by potentially serious side-effects of available endothelin-antagonists.


Assuntos
Endotelina-1/fisiologia , Glaucoma/fisiopatologia , Pressão Intraocular/fisiologia , Endotelina-1/antagonistas & inibidores , Olho/irrigação sanguínea , Glaucoma/tratamento farmacológico , Humanos , Pressão Intraocular/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia
12.
Curr Pharm Des ; 24(9): 983-988, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29384055

RESUMO

BACKGROUND: Preterm birth (PTB), defined as birth before 37 completed weeks of gestation, occurs in up to 18 percent of births worldwide and accounts for the majority of perinatal morbidity and mortality. While the single most common cause of PTB has been identified as inflammation, safe and effective pharmacotherapy to prevent PTB has yet to be developed. METHODS: Our group has used an in vivo model of inflammation-driven PTB, biochemical methods, pharmacological approaches, a novel endothelin receptor antagonist that we synthesized and RNA knockdown to help establish the role of endothelin-1 (ET-1) in inflammation-associated PTB. Further, we have used our in vivo model to test whether sphingosine kinase, which acts downstream of ET-1, plays a role in PTB. RESULTS: We have shown that levels of endothelin converting enzyme-1 (ECE-1) and ET-1 are increased when PTB is induced in timed pregnant mice with lipopolysaccharide (LPS) and that blocking ET-1 action, pharmacologically or using ECE-1 RNA silencing, rescues LPS-induced mice from PTB. ET-1 activates the sphingosine kinase/sphingosine-1-phosphate (SphK/S1P) pathway. S1P, in turn, is an important signaling molecule in the proinflammatory response. Interestingly, we have shown that SphK inhibition also prevents LPS-induced PTB in timed pregnant mice. Further, we showed that SphK inhibition suppresses the ECE-1/ET-1 axis, implicating positive feedback regulation of the SphK/S1P/ECE-1/ET-1 axis. CONCLUSION: The ET-1/SphK/SIP pathway is a potential pharmacotherapeutic target for the prevention of PTB.


Assuntos
Endotelina-1/metabolismo , Inflamação/metabolismo , Lisofosfolipídeos/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Nascimento Prematuro/metabolismo , Esfingosina/análogos & derivados , Animais , Endotelina-1/antagonistas & inibidores , Feminino , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Lisofosfolipídeos/antagonistas & inibidores , Camundongos , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Gravidez , Nascimento Prematuro/prevenção & controle , Esfingosina/antagonistas & inibidores , Esfingosina/metabolismo
13.
J Neurosci Res ; 96(1): 128-137, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28703856

RESUMO

Tissue-type plasminogen activator (tPA) is neurotoxic and exacerbates uncoupling of cerebral blood flow (CBF) and metabolism after stroke, yet it remains the sole FDA-approved drug for treatment of ischemic stroke. Upregulation of c-Jun-terminal kinase (JNK) after stroke contributes to tPA-mediated impairment of autoregulation, but the role of endothelin-1 (ET-1) is unknown. Based on the Glasgow Coma Scale, impaired autoregulation is linked to adverse outcomes after TBI, but correlation with hippocampal histopathology after stroke has not been established. We propose that given after stroke, tPA activates N-Methyl-D-Aspartate receptors (NMDA-Rs) and upregulates ET-1 in a JNK dependent manner, imparing autoregulation and leading to histopathology. After stroke, CBF was reduced in the hippocampus and reduced further during hypotension, which did not occur in hypotensive sham pigs, indicating impairment of autoregulation. Autoregulation and necrosis of hippocampal CA1 and CA3 neurons were further impaired by tPA, but were preserved by the ET-1 antagonist BQ 123 and tPA-A,296-299 a variant that is fibrinolytic but does not bind to NMDA-Rs. Expression of ET-1 was increased by stroke and potentiated by tPA but returned to sham levels by tPA-A296-299 and the JNK antagonist SP600125. Results show that JNK releases ET-1 after stroke. Tissue-type plasminogen activator -A296-299 prevents impairment of cerebral autoregulation and histopathology after stroke by inhibiting upregulation of ET-1.


Assuntos
Circulação Cerebrovascular/fisiologia , Endotelina-1/antagonistas & inibidores , Hipocampo/metabolismo , Homeostase/fisiologia , Acidente Vascular Cerebral/metabolismo , Ativador de Plasminogênio Tecidual/uso terapêutico , Animais , Circulação Cerebrovascular/efeitos dos fármacos , Endotelina-1/biossíntese , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Homeostase/efeitos dos fármacos , Masculino , Necrose , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia , Suínos , Ativador de Plasminogênio Tecidual/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
14.
Biomed Res Int ; 2017: 3137580, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29062837

RESUMO

Temporal consequences of neurocompensation to balloon injury on endothelinergic functionality in rat contralateral carotid were evaluated. Rats underwent balloon injury in left carotid and were treated with CP-96345 (NK1 antagonist). Concentration-response curves for endothelin-1 were obtained in contralateral (right) carotid at 2, 8, 16, 30, or 45 days after surgery in the absence or presence of BQ-123 (ETA antagonist), BQ-788 (ETB antagonist), or Tempol (superoxide-dismutase mimic). Endothelin-1-induced calcium mobilization was evaluated in functional assays carried out with BQ-123, BQ-788, or Tempol. Endothelin-1-induced NADPH oxidase-driven superoxide generation was measured by lucigenin chemiluminescence assays performed with BQ-123 or BQ-788. Endothelin-1-induced contraction was increased in contralateral carotid from the sixteenth day after surgery. This response was restored in CP-96345-treated rats. Endothelium removal or BQ-123 did not change endothelin-1-induced contraction in contralateral carotid. This response was restored by BQ-788 or Tempol. Contralateral carotid exhibited an increased endothelin-1-induced calcium mobilization, which was restored by BQ-788 or Tempol. Contralateral carotid exhibited an increased endothelin-1-induced lucigenin chemiluminescence, which was restored by BQ-788. We conclude that the NK1-mediated neurocompensatory response to balloon injury elicits a contractile hyperreactivity to endothelin-1 in rat contralateral carotid by enhancing the muscular ETB-mediated NADPH oxidase-driven generation of superoxide, which activates calcium channels.


Assuntos
Artérias Carótidas/fisiopatologia , Lesões das Artérias Carótidas/cirurgia , Endotelina-1/genética , Endotélio/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Acridinas/química , Animais , Compostos de Bifenilo/administração & dosagem , Cálcio/metabolismo , Artérias Carótidas/cirurgia , Lesões das Artérias Carótidas/tratamento farmacológico , Lesões das Artérias Carótidas/fisiopatologia , Óxidos N-Cíclicos/administração & dosagem , Endotelina-1/antagonistas & inibidores , Endotélio/metabolismo , Endotélio/cirurgia , Masculino , Oligopeptídeos/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Piperidinas/administração & dosagem , Ratos , Receptor de Endotelina A/genética , Marcadores de Spin , Superóxidos/metabolismo , Vasoconstrição/efeitos dos fármacos
15.
Mol Pharmacol ; 92(4): 481-490, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28778983

RESUMO

Nitro-fatty acids are reactive signaling mediators that are formed when unsaturated fatty acids react with nitric oxide or nitric oxide-derived species. Nitro-fatty acids can modify specific signaling pathways via post-translational modifications of Cys residues in key regulatory proteins. One of the signaling cascades activated by nitro-fatty acids is the Keap1-Nrf2 pathway. We have previously studied the effects of nitro-oleic acid (OA-NO2) on the human endothelial cell transcriptome. We observed that endothelin receptor B [ET-B (gene name EDNRB)], the receptor mediating the vasodilatory effects of endothelin-1 (ET-1) is induced by OA-NO2 Inasmuch as ET-1 is one of the key regulators of vascular tone, we chose to examine in more detail the effect of OA-NO2 on endothelin signaling in human endothelial cells. Nrf2 was found to regulate the OA-NO2-induced transcription of ET-B in human and mouse endothelial cells. Furthermore, chromatin immunoprecipitation analysis revealed that OA-NO2 increased the binding of Nrf2 to an antioxidant response element in the enhancer region of the EDNRB gene. In addition, we show that the overexpression of both OA-NO2 and Nrf2 substantially decreased and that Nrf2 silencing increased the ET-1 concentration in the culture media of endothelial cells. The change in the extracellular ET-1 concentration was dependent on ET-B receptor expression. These data suggest that OA-NO2 modulates endothelin signaling by increasing Nrf2-dependent expression of the ET-B receptor in endothelial cells, which in turn mediates the decrease in extracellular ET-1 concentration. Based on these results, we propose that OA-NO2 and Nrf2 may alleviate the vasoconstrictive effects of ET-1 by removing it from the circulation.


Assuntos
Células Endoteliais/metabolismo , Endotelina-1/metabolismo , Dióxido de Nitrogênio/farmacologia , Ácido Oleico/farmacologia , Transdução de Sinais/fisiologia , Animais , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Endotelina-1/antagonistas & inibidores , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
J Cell Mol Med ; 21(12): 3670-3678, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28744974

RESUMO

Patients with ischaemic heart disease or chronic heart failure show altered levels of obestatin, suggesting a role for this peptide in human heart function. We have previously demonstrated that GH secretagogues and the ghrelin gene-derived peptides, including obestatin, exert cardiovascular effects by modulating cardiac inotropism and vascular tone, and reducing cell death and contractile dysfunction in hearts subjected to ischaemia/reperfusion (I/R), through the Akt/nitric oxide (NO) pathway. However, the mechanisms underlying the cardiac actions of obestatin remain largely unknown. Thus, we suggested that obestatin-induced activation of PI3K/Akt/NO and PKG signalling is implicated in protection of the myocardium when challenged by adrenergic, endothelinergic or I/R stress. We show that obestatin exerts an inhibitory tone on the performance of rat papillary muscle in both basal conditions and under ß-adrenergic overstimulation, through endothelial-dependent NO/cGMP/PKG signalling. This pathway was also involved in the vasodilator effect of the peptide, used both alone and under stress induced by endothelin-1. Moreover, when infused during early reperfusion, obestatin reduced infarct size in isolated I/R rat hearts, through an NO/PKG pathway, comprising ROS/PKC signalling, and converging on mitochondrial ATP-sensitive potassium [mitoK(ATP)] channels. Overall, our results suggest that obestatin regulates cardiovascular function in stress conditions and induces cardioprotection by mechanisms dependent on activation of an NO/soluble guanylate cyclase (sGC)/PKG pathway. In fact, obestatin counteracts exaggerated ß-adrenergic and endothelin-1 activity, relevant factors in heart failure, suggesting multiple positive effects of the peptide, including the lowering of cardiac afterload, thus representing a potential candidate in pharmacological post-conditioning.


Assuntos
Cardiotônicos/farmacologia , Infarto do Miocárdio/prevenção & controle , Isquemia Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Óxido Nítrico/metabolismo , Hormônios Peptídicos/farmacologia , Animais , Cardiotônicos/química , Cardiotônicos/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Endotelina-1/antagonistas & inibidores , Endotelina-1/farmacologia , Regulação da Expressão Gênica , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Masculino , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Técnicas de Cultura de Órgãos , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/metabolismo , Músculos Papilares/patologia , Hormônios Peptídicos/genética , Hormônios Peptídicos/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Canais de Potássio/genética , Canais de Potássio/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Guanilil Ciclase Solúvel/genética , Guanilil Ciclase Solúvel/metabolismo
17.
Cell Physiol Biochem ; 42(5): 1802-1811, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28750371

RESUMO

BACKGROUND/AIMS: Endothelin-1 is implicated in the pathogenesis of hypertension, but the underlying mechanisms remained elusive. Our previous study found that inhibition of mitochondrial fission of smooth muscle cells suppressed phenylephrine- and high K+-induced artery constriction. Here, we studied the effects of mitochondrial fission inhibitors on endothelin-1-induced vasoconstriction. METHODS: The tension of rat mesenteric arteries and thoracic aorta was measured by using a multi-wire myograph system. Mitochondrial morphology of aortic smooth muscle cells was observed by using transmission electron microscopy. RESULTS: Dynamin-related protein-1 selective inhibitor mdivi-1 relaxed endothelin-1-induced constriction, and mdivi-1 pre-treatment prevented endothelin-1-induced constriction of rat mesenteric arteries with intact and denuded endothelium. Mdivi-1 had a similar inhibitory effect on rat thoracic aorta. Another mitochondrial fission inhibitor dynasore showed similar effects as mdivi-1 in rat mesenteric arteries. Mdivi-1 inhibited endothelin-1-induced increase of mitochondrial fission in smooth muscle cells of rat aorta. Rho-associated protein kinase inhibitor Y-27632 which relaxed endothelin-1-induced vasoconstriction inhibited endothelin-1-induced mitochondrial fission in smooth muscle cells of rat aorta. CONCLUSION: Endothelin-1 increases mitochondrial fission in vascular smooth muscle cells, and mitochondrial fission inhibitors suppress endothelin-1-induced vasoconstriction.


Assuntos
Aorta Torácica/fisiologia , Endotelina-1/metabolismo , Artérias Mesentéricas/fisiologia , Dinâmica Mitocondrial/efeitos dos fármacos , Quinazolinonas/farmacologia , Amidas/farmacologia , Animais , Aorta Torácica/citologia , Aorta Torácica/efeitos dos fármacos , Dinaminas/antagonistas & inibidores , Dinaminas/metabolismo , Endotelina-1/antagonistas & inibidores , Hidrazonas/farmacologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Mitocôndrias/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Vasoconstrição/efeitos dos fármacos
18.
Mol Biosyst ; 13(8): 1469-1480, 2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28604846

RESUMO

Traditional Chinese medicine (TCM) preparations have significant effects on some refractory diseases; however, these compositions are complex and their mechanisms are unknown. Identification of the active components in these preparations is essential. The mortality rate for heart failure (HF) has been increasing in recent years, and myocardial dysfunction (MD) has been proved to be the pathological basis of HF. Yixinshu Capsule (YXSC) is a multi-component oral drug with therapeutic effects on HF. However, the key active components are still unclear. In this study, YXSC intestinal absorption liquid (IAL) was used and 62 compounds were identified by an analytical chemistry approach. Then, a compound - target - function network was established with a bioinformatics analysis tool. Finally, a cell model of MD on human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) was used to verify the therapeutic effects of the active components of YXSC. Schisandrin A (Sch A) and schisandrin B (Sch B) were demonstrated to be the active components of YXSC by attenuating endothelin-1 (ET-1)-induced contraction dysfunction, brain natriuretic peptide (BNP) content elevation, and the morphological changes of hiPS-CMs. For the first time, our data illustrate the potent protective effects of Sch A and Sch B on ET-1-induced dysfunctional hiPS-CMs and revealed their effective targets and pathways. The integrative approach used in our study was applied to identify active components in TCM preparations and excavate the possible mechanisms.


Assuntos
Cardiotônicos/farmacologia , Ciclo-Octanos/farmacologia , Medicamentos de Ervas Chinesas/química , Antagonistas dos Receptores de Endotelina/farmacologia , Lignanas/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Compostos Policíclicos/farmacologia , Actinina/antagonistas & inibidores , Actinina/genética , Actinina/metabolismo , Animais , Bosentana , Cardiotônicos/química , Cardiotônicos/isolamento & purificação , Diferenciação Celular , Linhagem Celular , Ciclo-Octanos/química , Ciclo-Octanos/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Antagonistas dos Receptores de Endotelina/química , Antagonistas dos Receptores de Endotelina/isolamento & purificação , Endotelina-1/antagonistas & inibidores , Endotelina-1/farmacologia , Regulação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Lignanas/química , Lignanas/isolamento & purificação , Masculino , Medicina Tradicional Chinesa , Redes e Vias Metabólicas/efeitos dos fármacos , Metaboloma , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Peptídeo Natriurético Encefálico/antagonistas & inibidores , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/metabolismo , Compostos Policíclicos/química , Compostos Policíclicos/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Troponina T/antagonistas & inibidores , Troponina T/genética , Troponina T/metabolismo
19.
Pharmacol Rep ; 69(1): 139-142, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27919002

RESUMO

BACKGROUND: Our previous study showed that the µ-opioid receptor agonist fentanyl citrate inhibits endothelin-1-and bradykinin-mediated pain responses in mice orthotopically inoculated with melanoma cells. We also demonstrated that bradykinin induces endothelin-1 secretion in melanoma cells. However, the analgesic mechanisms of fentanyl citrate remain unclear. Thus, the present study was conducted to determine whether fentanyl citrate affects bradykinin-induced endothelin-1 secretion in B16-BL6 melanoma cells. METHODS: The amount of endothelin-1 in the culture medium was measured using an enzyme immunoassay. The expression of endothelin-1, kinin B2 receptors, and µ-opioid receptors in B16-BL/6 melanoma cells was determined using immunocytochemistry. RESULTS: Fentanyl citrate inhibited bradykinin-induced endothelin-1 secretion. The inhibitory effect of fentanyl citrate on the secretion of endothelin-1 was attenuated by the µ-opioid receptor antagonist naloxone methiodide. The immunoreactivities of endothelin-1, kinin B2 receptors, and µ-opioid receptors in B16-BL6 melanoma cells were observed. CONCLUSION: These results suggest that fentanyl citrate regulates bradykinin-induced endothelin-1 secretion through µ-opioid receptors in melanoma cells.


Assuntos
Analgésicos Opioides/farmacologia , Bradicinina/farmacologia , Endotelina-1/antagonistas & inibidores , Endotelina-1/metabolismo , Fentanila/farmacologia , Melanoma Experimental/metabolismo , Animais , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos C57BL , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo
20.
Hum Gene Ther ; 28(2): 190-199, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27736201

RESUMO

Cold temperatures are associated with increased prevalence of hypertension. Cold exposure increases endothelin-1 (ET1) production. The purpose of this study is to determine whether upregulation of ET1 contributes to cold-induced hypertension (CIH). In vivo RNAi silencing of the ET1 gene was achieved by adeno-associated virus 2 (AAV2) delivery of ET1 short-hairpin small interfering RNA (ET1-shRNA). Four groups of male rats were used. Three groups were given AAV.ET1-shRNA, AAV.SC-shRNA (scrambled shRNA), and phosphate-buffered saline (PBS), respectively, before exposure to a moderately cold environment (6.7 ± 2°C), while the last group was given PBS and kept at room temperature (warm, 24 ± 2°C) and served as a control. We found that systolic blood pressure of the PBS-treated and SC-shRNA-treated groups increased significantly within 2 weeks of exposure to cold, reached a peak level (145 ± 4.8 mmHg) by 6 weeks, and remained elevated thereafter. By contrast, blood pressure of the ET1-shRNA-treated group did not increase, suggesting that silencing of ET1 prevented the development of CIH. Animals were euthanized after 10 weeks of exposure to cold. Cold exposure significantly increased the left ventricle (LV) surface area and LV weight in cold-exposed rats, suggesting LV hypertrophy. Superoxide production in the heart was increased by cold exposure. Interestingly, ET1-shRNA prevented cold-induced superoxide production and cardiac hypertrophy. ELISA assay indicated that ET1-shRNA abolished the cold-induced upregulation of ET1 levels, indicating effective silencing of ET1. In conclusion, upregulation of ET1 plays a critical role in the pathogenesis of CIH and cardiac hypertrophy. AAV delivery of ET1-shRNA is an effective therapeutic strategy for cold-related cardiovascular disease.


Assuntos
Temperatura Baixa/efeitos adversos , Dependovirus/genética , Endotelina-1/antagonistas & inibidores , Terapia Genética , Vetores Genéticos/administração & dosagem , Hipertensão/terapia , RNA Interferente Pequeno/genética , Animais , Endotelina-1/genética , Humanos , Hipertensão/etiologia
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