Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.385
Filtrar
1.
Endocrinology ; 160(9): 2165-2179, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31310273

RESUMO

Viruses have developed different mechanisms to manipulate their hosts, including the process of viral mimicry in which viruses express important host proteins. Until recently, examples of viral mimicry were limited to mimics of growth factors and immunomodulatory proteins. Using a comprehensive bioinformatics approach, we have shown that viruses possess the DNA/RNA with potential to encode 16 different peptides with high sequence similarity to human peptide hormones and metabolically important regulatory proteins. We have characterized one of these families, the viral insulin/IGF-1-like peptides (VILPs), which we identified in four members of the Iridoviridae family. VILPs can bind to human insulin and IGF-1 receptors and stimulate classic postreceptor signaling pathways. Moreover, VILPs can stimulate glucose uptake in vitro and in vivo and stimulate DNA synthesis. DNA sequences of some VILP-carrying viruses have been identified in the human enteric virome. In addition to VILPs, sequences with homology to 15 other peptide hormones or cytokines can be identified in viral DNA/RNA sequences, some with a very high identity to hormones. Recent data by others has identified a peptide that resembles and mimics α-melanocyte-stimulating hormone's anti-inflammatory effects in in vitro and in vivo models. Taken together, these studies reveal novel mechanisms of viral and bacterial pathogenesis in which the microbe can directly target or mimic the host endocrine system. These findings also introduce the concept of a system of microbial hormones that provides new insights into the evolution of peptide hormones, as well as potential new roles of microbial hormones in health and disease.


Assuntos
Interações Hospedeiro-Patógeno/fisiologia , Fator de Crescimento Insulin-Like I/fisiologia , Proteínas Virais/fisiologia , Animais , Endocrinologia , Endotelina-1/fisiologia , Doenças dos Peixes/etiologia , Humanos , Fator de Crescimento Insulin-Like I/química , Proteínas Virais/química
2.
Osteoporos Int ; 30(8): 1699-1703, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31079185

RESUMO

We report a 46-yr-old woman with a history of breast cancer who presented with diffuse myalgias, bone pain, and osteosclerosis. She was found to have recurrent breast cancer producing endothelin-1. INTRODUCTION: Acquired osteosclerosis can be caused by various disorders. Endothelin -1 is believed to contribute to osteosclerosis caused by breast cancer. METHODS: Although the bone marrow biopsy did not reveal breast cancer, she developed skin lesions consistent with metastatic breast cancer. She ultimately died from progressive disease. At autopsy immunohistochemistry for endothelin-1 was performed on a section from the L5 vertebral body. RESULTS: The section from the L5 vertebral body showed small foci of cells consistent with metastatic carcinoma and a prominent sclerotic response. Immunohistochemistry for endothelin-1 was strongly positive. CONCLUSIONS: Recurrent breast cancer may present with diffuse osteosclerosis. Endothelin-1 may be a paracrine factor responsible for increased bone formation and osteosclerosis.


Assuntos
Adenocarcinoma/secundário , Neoplasias Ósseas/secundário , Neoplasias da Mama/metabolismo , Endotelina-1/fisiologia , Osteosclerose/etiologia , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Neoplasias Ósseas/complicações , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/metabolismo , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Osteosclerose/diagnóstico por imagem , Osteosclerose/metabolismo , Radiografia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/secundário
3.
J Vet Med Sci ; 81(2): 263-268, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30606891

RESUMO

Cardiac biomarkers are important tools for monitoring disease progress and can monitor progression of therapy. Endothelin-1 (ET-1) has been studied for its use as a cardiac biomarker in human and small animal medicine while in horses with cardiac disease it has not been evaluated yet. The objective of the present study was to determine the concentration of plasma ET-1 in healthy horses and compare it with ET-1 concentration in horses with cardiac disease during rest and after exercise. Fifty four horses admitted to the Equine Clinic of Free University of Berlin were used in the present study, of which 15 horses were clinically healthy with no evidence of cardiac disease (Group 1), 22 horses suffered from cardiac disease with normal heart dimensions (Group 2) and 17 horses with cardiac disease and enlarged heart diameters (Group 3). Clinical examination, electrocardiography and echocardiography were performed. Endothelin-1 concentration was determined using ET-1 ELISA kit. The concentration of plasma ET-1 was significantly increased in horses with cardiac disease and normal cardiac dimensions (Group 2) and in horses with cardiac disease and enlargement of the left atrium (Group 3) compared to its concentration in clinically healthy horses (Group 1). In addition, the concentration of plasma ET-1 after exercise was significantly increased in diseased horses compared to its concentration at rest. Detection of ET-1 plasma concentration in horses at rest may be useful for detecting horses with changes in left atrial cardiac dimensions.


Assuntos
Endotelina-1/sangue , Cardiopatias/veterinária , Doenças dos Cavalos/fisiopatologia , Cavalos/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Biomarcadores/sangue , Ecocardiografia/veterinária , Eletrocardiografia/veterinária , Endotelina-1/fisiologia , Feminino , Cardiopatias/sangue , Cardiopatias/fisiopatologia , Doenças dos Cavalos/sangue , Cavalos/sangue , Masculino , Descanso/fisiologia
4.
J Clin Endocrinol Metab ; 104(2): 341-348, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30165404

RESUMO

Context: Endothelium guarantees vascular homeostasis by the opposite action of substances by vasodilating/antithrombogenic and vasoconstricting/prothrombotic activities. Obesity is characterized by endothelial dysfunction associated with a condition of vascular low-grade inflammation. Evidence Acquisition: Analysis of available basic or clinical papers published in peer-reviewed international journals on microcirculation and obesity. Evidence Synthesis: Vascular low-grade inflammation, which characterizes obesity, is secondary to abnormal production of proinflammatory cytokines, including TNF-α. TNF-α, generated either in small vessels or within the perivascular adipose tissue (PVAT) of patients with obesity, stimulates reactive oxygen species generation, mainly through NAD(P)H oxidase activation, which in turn reduces nitric oxide (NO) availability. These aspects are highlighted by the insulin resistance status and macronutrient intake that characterize the obesity condition. Oxidant excess has also been proposed as a mechanism whereby TNF-α interferes with the endothelin-1/NO system at the level of small vessels from patients with obesity. Conclusions: In obesity, microvasculature from visceral fat is an important source of low-grade inflammation and oxidative stress that, together with the PVAT, directly contribute to vascular changes, favoring the development and acceleration of the vascular atherothrombotic process in this clinical condition.


Assuntos
Endotélio Vascular/fisiopatologia , Obesidade/fisiopatologia , Fator de Necrose Tumoral alfa/fisiologia , Tecido Adiposo/fisiopatologia , Endotelina-1/fisiologia , Humanos , Inflamação/etiologia , Inflamação/fisiopatologia , Insulina/fisiologia , Resistência à Insulina/fisiologia , Microvasos/fisiopatologia , Obesidade/complicações , Estresse Oxidativo/fisiologia
5.
Mol Biol Rep ; 46(1): 199-205, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30411193

RESUMO

The endothelin (EDN) axis (EDN1 and EDN1 receptor A, EDNRA) is involved in cellular growth, differentiation, invasiveness, and tumor progression in several cancers. We wanted to examine the possible impact of single nucleotide polymorphisms (SNPs) of EDN1 and EDNRA genes on papillary thyroid cancer (PTC) development and general characteristics of PTC. Study population consist of 113 PTC patients and 185 controls. EDN1 (G5665T, T-1370G) and EDNRA (C TT70G, G-231A) SNPs were investigated by real-time PCR. The GG genotype of EDNRA + 70 SNP was associated with threefold increased PTC risk (p = 0.01), and the combined CG + GG genotype was 2.48 fold higher among PTC patients compared to controls. The variant EDNRA - 231 allele was overrepresented in PTC patients according to controls (p = 0.05). The combined GT + TT genotype of EDN1 5665 SNP was related with late (age after 40 years) PTC onset (p = 0.04), and was more prominent among male patients with PTC according to females (p = 0.03). No significant associations between PTC and - 1370 SNP were found. There were no relationships between laboratory parameters and investigated polymorphisms. The EDNRA + 70 SNP was associated with PTC development. The EDN1 5665 SNP was linked with increased risk for late PTC onset and was more prominent among male patients with PTC.


Assuntos
Endotelina-1/genética , Receptor de Endotelina A/genética , Câncer Papilífero da Tireoide/genética , Adulto , Idoso , Alelos , Endotelina-1/fisiologia , Endotelinas/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Receptor de Endotelina A/fisiologia , Receptores de Endotelina/genética , Fatores de Risco , Neoplasias da Glândula Tireoide
6.
Sheng Li Xue Bao ; 70(4): 354-360, 2018 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-30112560

RESUMO

The purpose of this study is to investigate the effect of the oral endothelin antagonist Bosentan on blood pressure and renal sympathetic nerve activity (RSNA) in rats exposed to chronic intermittent hypoxia (CIH), and to explore the sympathoexcitation mechanism of endothelin-1 (ET-1) in CIH-induced hypertension. Twenty-four male SD rats were randomly divided into normoxia, CIH and Bosentan groups. Rats in the normoxia group were exposed to normoxic environment, and rats in CIH or Bosentan group were exposed to intermittent hypoxia for 3 weeks. Bosentan was given at 50 mg/kg by intragastric administration before intermittent hypoxia exposure in Bosentan group. Systolic blood pressure (SBP) was measured by BP-2000, and the change of RSNA to sodium nitroprusside (SNP) or phenylephrine (PE) was recorded by PowerLab signal acquisition system. Serums of all rats were collected and the contents of ET-1 and norepinephrine (NE) were measured by ELISA. Results showed that blood pressure was gradually increased following CIH exposure compared with the normoxia group during the 3 weeks (P < 0.01, P < 0.01, P < 0.001). The basal RSNA was increased and baroreflex sensitivity was decreased in rats exposed to CIH. Furthermore, the blood pressure was positively correlated with the level of ET-1 in serum in rats exposed to CIH (r = 0.833, P = 0.01). Bosentan administration significantly decreased SBP and basal RSNA, increased the baroreflex sensitivity, and decreased serum NE level in rats exposed to CIH. These results suggest that ET-1 is related with blood pressure elevation in rats exposed to CIH, and Bosentan reverses CIH-induced hypertension by decreasing RSNA.


Assuntos
Bosentana/farmacologia , Hipertensão/tratamento farmacológico , Hipóxia/fisiopatologia , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Barorreflexo , Pressão Sanguínea , Endotelina-1/fisiologia , Rim/efeitos dos fármacos , Rim/inervação , Masculino , Nitroprussiato/farmacologia , Fenilefrina/farmacologia , Ratos , Ratos Sprague-Dawley
7.
J Vasc Res ; 55(4): 210-223, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30071538

RESUMO

Age-associated structural and functional remodeling of the arterial wall produces a productive environment for the initiation and progression of hypertension and atherosclerosis. Chronic aging stress induces low-grade proinflammatory signaling and causes cellular proinflammation in arterial walls, which triggers the structural phenotypic shifts characterized by endothelial dysfunction, diffuse intimal-medial thickening, and arterial stiffening. Microscopically, aged arteries exhibit an increase in arterial cell senescence, proliferation, invasion, matrix deposition, elastin fragmentation, calcification, and amyloidosis. These characteristic cellular and matrix alterations not only develop with aging but can also be induced in young animals under experimental proinflammatory stimulation. Interestingly, these changes can also be attenuated in old animals by reducing low-grade inflammatory signaling. Thus, mitigating age-associated proinflammation and arterial phenotype shifts is a potential approach to retard arterial aging and prevent the epidemic of hypertension and atherosclerosis in the elderly.


Assuntos
Envelhecimento/fisiologia , Artérias/fisiopatologia , Inflamação/fisiopatologia , Rigidez Vascular/fisiologia , Animais , Artérias/patologia , Aterosclerose/fisiopatologia , Aterosclerose/prevenção & controle , Células Endoteliais/fisiologia , Endotelina-1/fisiologia , Endotélio Vascular/fisiopatologia , Humanos , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Inflamação/prevenção & controle , Fenótipo , Sistema Renina-Angiotensina/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Síndrome
8.
Curr Hypertens Rep ; 20(7): 58, 2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29884912

RESUMO

PURPOSE OF REVIEW: Men and women differ in the prevalence, pathophysiology and control rate of hypertension in an age-dependent manner. The renal endothelin system plays a central role in sex differences in blood pressure regulation by control of sodium excretion and vascular function. Improving our understanding of the sex differences in the endothelin system, especially in regard to blood pressure regulation and sodium homeostasis, will fill a significant gap in our knowledge and may identify sex-specific therapeutic targets for management of hypertension. RECENT FINDINGS: The current review will highlight evidence for the potential role for endothelin system in the pathophysiology of hypertension within three female populations: (i) postmenopausal women, (ii) women suffering from preeclampsia, or (iii) pulmonary arterial hypertension. Clinical trials that specifically address cardiovascular and renal diseases in females under different hormonal status are limited. Studies of the modulatory role of gonadal hormones and sex-specific mechanisms on critically important systems involved, such as endothelin, are needed to establish new clinical practice guidelines based on systematic evidence.


Assuntos
Pressão Sanguínea/fisiologia , Endotelina-1/fisiologia , Hipertensão/fisiopatologia , Adulto , Fatores Etários , Idoso , Feminino , Homeostase/fisiologia , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pós-Menopausa/fisiologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Fatores de Risco , Caracteres Sexuais , Sódio/sangue
9.
Physiol Res ; 67(Suppl 1): S115-S125, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29947532

RESUMO

Endothelial cells (ECs) are primary targets of glucose-induced tissue damage. As a result of hyperglycemia, endothelin-1 (ET-1) is upregulated in organs affected by chronic diabetic complications. The objective of the present study was to identify novel transcriptional mechanisms that influence ET-1 regulation in diabetes. We carried out the investigation in microvascular ECs using multiple approaches. ECs were incubated with 5 mM glucose (NG) or 25 mM glucose (HG) and analyses for DNA methylation, histone methylation, or long non-coding RNA- mediated regulation of ET-1 mRNA were then performed. DNA methylation array analyses demonstrated the presence of hypomethylation in the proximal promoter and 5' UTR/first exon regions of EDN1 following HG culture. Further, globally blocking DNA methylation or histone methylation significantly increased ET-1 mRNA expressions in both NG and HG-treated HRECs. While, knocking down the pathogenetic lncRNAs ANRIL, MALAT1, and ZFAS1 subsequently prevented the glucose-induced upregulation of ET-1 transcripts. Based on our past and present findings, we present a novel paradigm that reveals a complex web of epigenetic mechanisms regulating glucose-induced transcription of ET-1. Improving our understanding of such processes may lead to better targeted therapies.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Células Endoteliais/metabolismo , Endotelina-1/fisiologia , Epigênese Genética/fisiologia , Glucose/toxicidade , Animais , Células Cultivadas , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Células Endoteliais/efeitos dos fármacos , Endotelina-1/agonistas , Epigênese Genética/efeitos dos fármacos , Humanos
10.
Per Med ; 15(1): 25-33, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29714117

RESUMO

AIM: The predictive value of big endothelin-1 (ET-1) for cardiovascular outcomes in myocardial infarction (MI) patients younger than 35 years old has not been characterized. METHODS: A total of 565 consecutive MI patients younger than 35 years old were studied and followed up for 37.78 ± 24.9 months. RESULTS: Multivariable Cox regression analysis showed that big ET-1 was positively correlated with major adverse cardiovascular events [MACEs] (odds ratio: 3; 95% CI: 1.92-4.68; p < 0.001). The area under receiver operating characteristics curve showing the predictive value of big ET-1 on MACEs was 0.67. CONCLUSION: The study first demonstrated that big ET-1 was an independent predictor for MACEs in MI patients younger than 35 years old.


Assuntos
Endotelina-1/metabolismo , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Adulto , China/epidemiologia , Endotelina-1/fisiologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Infarto do Miocárdio/patologia , Razão de Chances , Intervenção Coronária Percutânea/efeitos adversos , Prognóstico , Curva ROC , Análise de Regressão , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
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.
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
13.
Br J Haematol ; 178(5): 781-793, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28597546

RESUMO

New effective treatments are needed to improve outcomes for multiple myeloma (MM) patients. Receptors with restricted expression on plasma cells (PCs) represent attractive new therapeutic targets. The endothelin-1 (EDN1) axis, consisting of EDN1 acting through EDN-receptor A (EDNRA) and B (EDNRB), was previously shown to be overexpressed in several tumours, including MM. However, there is incomplete understanding of how EDN1 axis regulates MM growth and response to therapy. Besides EDNRA, the majority of MM cell lines and primary malignant PCs express high levels of EDNRB and release EDN1. Similarly, bone-marrow microenvironment cells also secrete EDN1. Investigating the extent of epigenetic dysregulation of EDNRB gene in MM, we found that hypermethylation of EDNRB promoter and subsequent down-regulation of EDNRB gene was observed in PCs or B lymphocytes from healthy donors compared to EDNRB-expressing malignant PCs. Pharmacological blockade with the dual EDN1 receptor antagonist bosentan decreased cell viability and MAPK activation of U266 and RPMI-8226 cells. Interestingly, the combination of bosentan and the proteasome inhibitor bortezomib, currently approved for MM treatment, resulted in synergistic cytotoxic effects. Overall, our data has uncovered EDN1-mediated autocrine and paracrine mechanisms that regulate malignant PCs growth and drug response, and support EDN1 receptors as new therapeutic targets in MM.


Assuntos
Antagonistas do Receptor de Endotelina A/farmacologia , Mieloma Múltiplo/sangue , Receptor de Endotelina A/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Comunicação Autócrina/fisiologia , Bortezomib/farmacologia , Bosentana , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Metilação de DNA , DNA de Neoplasias/genética , Sinergismo Farmacológico , Endotelina-1/sangue , Endotelina-1/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Plasmócitos/metabolismo , Regiões Promotoras Genéticas , Receptor de Endotelina A/genética , Sulfonamidas/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/patologia
14.
J Hypertens ; 35(6): 1204-1212, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28441692

RESUMO

OBJECTIVES: The current study addressed the hypothesis that the local decrease in endothelin-1 (ET-1) bioavailability during sustained flow increases contributes to endothelium-dependent, flow-mediated dilatation (FMD) of conduit arteries and is altered in presence of cardiovascular risk factors. METHODS AND RESULTS: In nine young healthy individuals, the decrease in local ET-1 plasma levels and radial artery FMD in response to hand skin heating (from 34 to 44 °C) was not affected by endothelin type A (ETA) receptor blockade, achieved using the brachial infusion of BQ-123 (100 nmol/min per l of forearm), as compared with physiological saline (0.9% NaCl) infusion. In contrast, endothelin type B (ETB) receptor blockade with BQ-788 (10 nmol/min per l) suppressed the decrease in plasma ET-1 during heating and reduced FMD, without altering nitric oxide release. The coinfusion of BQ-123 did not affect the inhibitory effect of ETB receptor blockade on the decrease in ET-1 plasma levels during heating but prevented the reduction in FMD. Basal radial artery parameters, systemic hemodynamics, and endothelium-independent dilatation to glyceryl trinitrate were not modified by ETA and/or ETB blockade. In a general population of 40 participants without treatment or major cardiovascular diseases, including the nine healthy individuals, the reduction in endothelin-1 level during heating was correlated with FMD (r = -0.55, P < 0.001) and decreased with increased age (r = 0.49, P = 0.001), mean arterial blood pressure (r = 0.48, P = 0.002), and total cholesterol level (r = 0.37, P = 0.024). CONCLUSION: The uptake of endothelin-1 by ETB receptors contributes to conduit artery FMD, preventing its vasoconstrictor action mediated by ETA receptors. The alteration of this mechanism by cardiovascular risk factors may contribute to endothelial dysfunction.


Assuntos
Endotelina-1/fisiologia , Vasodilatação/fisiologia , Adulto , Doenças Cardiovasculares , Antagonistas do Receptor de Endotelina A/farmacologia , Antagonistas do Receptor de Endotelina B/farmacologia , Antagonistas dos Receptores de Endotelina/farmacologia , Feminino , Hemodinâmica/fisiologia , Humanos , Masculino , Óxido Nítrico/metabolismo , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Piperidinas/farmacologia , Fatores de Risco , Vasodilatação/efeitos dos fármacos , Adulto Jovem
15.
Curr Hypertens Rev ; 13(1): 33-40, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28413991

RESUMO

Early vascular aging is a process associated with gradual alterations in the vessels, regarding their structure and function, taking a more rapid course than normal biological aging in the arteries. In the presence of cardiovascular disease, these age-associated alterations are accelerated, contributing in the appearance or the progression of cardiovascular disease, such as high blood pressure, dyslipidemia, smoking and diabetes. Endothelin-1 (ET-1) is the most abundant and important endothelin produced by vascular cells. ET-1 exerts its biological actions through the activation of two receptors: ETA and ETB. Many important functions are mediated by the activation of these receptors, such as cardiovascular remodeling, vasoconstriction, cell proliferation and differentiation, production of extracellular matrix, and water and sodium secretion control. ETA receptor seems to participate in the pathogenesis and development of diseases, such as diabetes, atherosclerosis, systemic and pulmonary hypertension, and cardiac remodeling after myocardial ischemia, whereas ETB receptor seems to prevent the overstimulation of ETA receptor, acting as a clearance receptor. Increased ET-1 system activity may contribute to vascular dysfunction in aging via multiple pathways, such as direct hemodynamic effects, vascular oxidative stress, inflammatory activity, mitogenic stimulation of the vascular smooth muscle cells and fibrotic processes. Endothelin receptor antagonists were considered to be used for the treatment of some diseases like hypertension, diabetes and chronic kidney disease. However, besides pulmonary hypertension, this class is not in clinical use because of the side effects and the availability of safer drugs for the treatment of these diseases.


Assuntos
Envelhecimento/fisiologia , Vasos Sanguíneos/fisiopatologia , Antagonistas dos Receptores de Endotelina/uso terapêutico , Endotelina-1/fisiologia , Hipertensão/tratamento farmacológico , Vasos Sanguíneos/patologia , Doenças Cardiovasculares/etiologia , Progressão da Doença , Endotelinas/fisiologia , Humanos , Hipertensão/etiologia , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Músculo Liso Vascular , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Vasoconstrição/fisiologia
16.
J Physiol ; 595(8): 2535-2550, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28120456

RESUMO

KEY POINTS: Hypercalcaemia can occur under various pathological conditions, such as primary hyperparathyroidism, malignancy or granulomatosis, and it induces natriuresis and polyuria in various species via an unknown mechanism. A previous study demonstrated that hypercalcaemia induced by vitamin D in rats increased endothelin (ET)-1 expression in the distal nephron, which suggests the involvement of the ET system in hypercalcaemia-induced effects. In the present study, we demonstrate that, during vitamin D-induced hypercalcaemia, the activation of ET system by increased ET-1 is responsible for natriuresis but not for polyuria. Vitamin D-treated hypercalcaemic mice showed a blunted response to amiloride, suggesting that epithelial sodium channel function is inhibited. We have identified an original pathway that specifically mediates the effects of vitamin D-induced hypercalcaemia on sodium handling in the distal nephron without affecting water handling. ABSTRACT: Acute hypercalcaemia increases urinary sodium and water excretion; however, the underlying molecular mechanism remains unclear. Because vitamin D-induced hypercalcaemia increases the renal expression of endothelin (ET)-1, we hypothesized that ET-1 mediates the effects of hypercalcaemia on renal sodium and water handling. Hypercalcaemia was induced in 8-week-old, parathyroid hormone-supplemented, male mice by oral administration of dihydrotachysterol (DHT) for 3 days. DHT-treated mice became hypercalcaemic and displayed increased urinary water and sodium excretion compared to controls. mRNA levels of ET-1 and the transcription factors CCAAT-enhancer binding protein ß and δ were specifically increased in the distal convoluted tubule and downstream segments in DHT-treated mice. To examine the role of the ET system in hypercalcaemia-induced natriuresis and polyuria, mice were treated with the ET-1 receptor antagonist macitentan, with or without DHT. Mice treated with both macitentan and DHT displayed hypercalcaemia and polyuria similar to that in mice treated with DHT alone; however, no increase in urinary sodium excretion was observed. To identify the affected sodium transport mechanism, we assessed the response to various diuretics in control and DHT-treated hypercalcaemic mice. Amiloride, an inhibitor of the epithelial sodium channel (ENaC), increased sodium excretion to a lesser extent in DHT-treated mice compared to control mice. Mice treated with either macitentan+DHT or macitentan alone had a similar response to amiloride. In summary, vitamin D-induced hypercalcaemia increases the renal production of ET-1 and decreases ENaC activity, which is probably responsible for the rise in urinary sodium excretion but not for polyuria.


Assuntos
Endotelina-1/fisiologia , Hipercalcemia/metabolismo , Natriurese/fisiologia , Poliúria/metabolismo , Vitamina D/toxicidade , Doença Aguda , Animais , Linhagem Celular Transformada , Hipercalcemia/induzido quimicamente , Hipercalcemia/urina , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Natriurese/efeitos dos fármacos , Poliúria/urina
17.
Endocrinol Metab Clin North Am ; 46(1): 51-62, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28131136

RESUMO

The endothelin (ET) system includes 3 small peptide hormones and a pair of G-protein-coupled receptors. This review first outlines the ET signaling pathway and ET metabolism. Next, it summarizes the role of ET1 signaling in craniofacial development. Then, it discusses observations relating ET signaling to osteoblastic and other osteosclerotic processes in cancer. Finally, it describes recent work in our laboratory that points to endothelin signaling as an upstream mediator of WNT signaling, promoting bone matrix synthesis and mineralization. It concludes with a statement of some remaining gaps in knowledge and proposals for future research.


Assuntos
Osso e Ossos/fisiologia , Endotelina-1/fisiologia , Osteogênese , Transdução de Sinais , Neoplasias Ósseas/metabolismo , Humanos
18.
Br J Pharmacol ; 174(22): 4032-4042, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27625162

RESUMO

BACKGROUND AND PURPOSE: The majority of the severe vascular complications in fibrosis are a consequence of a deregulated activity of mediators controlling vasomotor tone. One of the most important of these mediators is endothelin-1 (ET-1). Here, we have investigated the role of proteinase-activated receptor 2 (PAR2) in the vascular dysfunction in a model of fibrosis, using tight-skin (Tsk) mice. EXPERIMENTAL APPROACH: Aortas were collected from Tsk, transgenic over-expressing PAR2 (TgPAR2), PAR2 deficient (PAR2-/- ) or the corresponding WT mice. Histological and immunohistochemistry analysis for α-smooth muscle actin, PAR2 and ET-1 receptors were performed on aorta sections. Vascular responses to phenylephrine, ET-1 and PAR2 activating peptide (PAR2-AP) were assessed on aortic rings. KEY RESULTS: In aortas from Tsk mice, responses to phenylephrine were reduced, contractions to ET-1 were increased and vasorelaxation to PAR2-AP was enhanced. These alterations matched changes observed in whole vessel architecture such as vascular fibre re-organization, increased collagen deposition and enhanced α-smooth muscle actin expression. Expression of both ETA receptors and PAR2 was enhanced in Tsk mice. Antagonism of PAR2 potentiated vascular effects of ET-1, whereas antagonism of ETA receptors increased vasorelaxation induced by PAR2-AP. In TgPAR2 mice, responses to ET-1 and ET-1 plasma levels were reduced. Conversely, PAR2-/- mice showed enhanced ET-1 induced contraction in aortic rings and higher circulating ET-1 levels. CONCLUSIONS AND IMPLICATIONS: Our data show that PAR2 counterbalanced enhanced contractions to ET-1 in aortas from Tsk mice. PAR2 could represent a possible target for novel drugs in the treatment of vascular complications in fibrosis. LINKED ARTICLES: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.


Assuntos
Aorta Torácica/fisiologia , Endotelina-1/fisiologia , Receptor PAR-2/fisiologia , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Endotelina-1/sangue , Fibrose , Masculino , Camundongos , Camundongos Transgênicos , Receptor de Endotelina A/metabolismo , Receptor de Endotelina A/fisiologia , Receptor PAR-2/antagonistas & inibidores , Receptor PAR-2/genética
19.
Hipertens Riesgo Vasc ; 34(2): 78-84, 2017.
Artigo em Espanhol | MEDLINE | ID: mdl-27876299

RESUMO

INTRODUCTION: The endothelin system, for its vasoconstrictor action, is related to the development of essential hypertension (HTAe). The polymorphism analysis of their genes represents a new approach to the study of this disease. We propose to analyze the interaction between stages of essential hypertension (HTAe) and risk factors with polymorphisms 138ex1 ins/del A gene endothelin-1 (ET-1) and H323H receptor gene A ET-1 (ETRA). PATIENTS AND METHODS: We included 300 patients of both sexes, unrelated, who consecutively attended the clinic hypertension medical service. Each one underwent a complete physical examination, electrocardiogram, echocardiogram, and Rx thorax. The degree of severity of hypertension was determined in stages. The determination of polymorphisms was performed by amplification followed by cutting by specific restriction enzyme from DNA obtained from peripheral blood. RESULTS: The 46% of patients had HTAe controlled, 17.6% had organ damage or cardiovascular, brain or kidney disease. It was observed that the 4A/4A carriers showed lower frequency of cardiovascular disease, kidney and brain (P<.032; 95% CI: 11.1-21.4). For H323H polymorphism, the evaluation by images showed a higher frequency of the dilations of left auricular (P=.02) and auricular fibrillation (P=.03) between the T/T carrier, a higher frequency of cardiomegaly was detected in C/C patients (P=.04). CONCLUSION: The genotypes, 4A/4A of the ET-1 gene and the T/T from ETRA gene might be involved in worse outcome of cardiovascular damage. Their identification could help recognize subgroups of the hypertensive patients with different risk.


Assuntos
Endotelina-1/genética , Hipertensão Essencial/genética , Coração/fisiopatologia , Miocárdio/patologia , Polimorfismo de Nucleotídeo Único , Receptor de Endotelina A/genética , Idoso , Argentina/epidemiologia , Arritmias Cardíacas/etiologia , Cardiomegalia/etiologia , Endotelina-1/fisiologia , Hipertensão Essencial/complicações , Hipertensão Essencial/patologia , Feminino , Estudos de Associação Genética , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Endotelina A/fisiologia , Fatores de Risco , Índice de Gravidade de Doença , Volume Sistólico
20.
Physiol Rep ; 4(21)2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27905299

RESUMO

Therapeutic approaches to block the progression from acute kidney injury to chronic kidney disease are currently lacking. Endothelin-1 (ET-1) is a powerful vasoconstrictor, induced by hypoxia, and previously implicated in renal ischemia-reperfusion (IR) injury. This study tested the hypothesis that blunting the vascular influence of ET-1, either through endothelin ETA receptor blockade (ABT-627) or vascular endothelial cell deletion of ET-1 (VEET KO), would improve recovery of renal perfusion and repair of injury following a severe ischemic insult in mice (45 min unilateral renal ischemia). Male C57Bl/6 mice receiving vehicle or ABT-627 commencing 2 days prior to surgery, and VEET KO mice and wild-type littermates (WT) underwent 45 min unilateral renal IR surgery followed by 28 days recovery. Renal blood velocity was measured by pulsed-wave Doppler ultrasound before and after surgery. Renal blood velocity was not significantly different between pairs of groups before surgery. Unilateral IR induced a marked reduction in renal blood velocity of the IR kidney at 24 h postsurgery in all groups, which partially recovered but remained below baseline at 28 days post-IR. Despite the lack of effect on renal blood velocity, ETA receptor blockade significantly attenuated the atrophy of the post-IR kidney, whereas this was not significantly affected by lack of endothelial ET-1 expression. These data suggest that although blockade of the ETA receptor is mildly beneficial in preserving renal mass following a severe ischemic insult, this protective effect does not appear to involve improved recovery of renal perfusion.


Assuntos
Lesão Renal Aguda/metabolismo , Endotelina-1/genética , Endotelina-1/fisiologia , Rim/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Lesão Renal Aguda/cirurgia , Animais , Atrasentana , Velocidade do Fluxo Sanguíneo/fisiologia , Modelos Animais de Doenças , Progressão da Doença , Antagonistas dos Receptores de Endotelina/farmacologia , Isquemia , Rim/irrigação sanguínea , Rim/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Pirrolidinas/farmacologia , Insuficiência Renal Crônica/metabolismo , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/diagnóstico por imagem , Ultrassonografia Doppler de Pulso/métodos , Regulação para Cima/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA