RESUMO
ET (endothelin) is a powerful vasoconstrictor 21-amino acid peptide present in many tissues, which exerts many physiological functions across the body and participates as a mediator in many pathological conditions. ETs exert their effects through ETA and ETB receptors, which can be blocked by selective receptor antagonists. ETs were shown to play important roles among others, in systemic hypertension, particularly when resistant or difficult to control, and in pulmonary hypertension, atherosclerosis, cardiac hypertrophy, subarachnoid hemorrhage, chronic kidney disease, diabetic cardiovascular disease, scleroderma, some cancers, etc. To date, ET antagonists are only approved for the treatment of primary pulmonary hypertension and recently for IgA nephropathy and used in the treatment of digital ulcers in scleroderma. However, they may soon be approved for the treatment of patients with resistant hypertension and different types of nephropathy. Here, the role of ETs is reviewed with a special emphasis on participation in and treatment of hypertension and chronic kidney disease.
Assuntos
Hipertensão Pulmonar , Hipertensão , Insuficiência Renal Crônica , Humanos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Endotelinas , Hipertensão/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Endotelina-1/fisiologia , Receptores de Endotelina , Receptor de Endotelina ARESUMO
There is accumulating evidence of autonomic dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); however, little is known about its association with circadian rhythms and endothelial dysfunction. This study aimed to explore the autonomic responses through an orthostatic test and analysis of the peripheral skin temperature variations and vascular endothelium state in ME/CFS patients. Sixty-seven adult female ME/CFS patients and 48 healthy controls were enrolled. Demographic and clinical characteristics were assessed using validated self-reported outcome measures. Postural changes in blood pressure, heart rate, and wrist temperature were recorded during the orthostatic test. Actigraphy during one week was used to determine the 24-h profile of peripheral temperature and activity. Circulating endothelial biomarkers were measured as indicators of endothelial functioning. Results showed that ME/CFS patients presented higher blood pressure and heart rate values than healthy controls in the supine and standing position (p < 0.05 for both), and also a higher amplitude of the activity rhythm (p < 0.01). Circulating levels of endothelin-1 (ET-1) and vascular cell adhesion molecule-1 (VCAM-1) were significantly higher in ME/CFS (p < 0.05). In ME/CFS, ET-1 levels were associated with the stability of the temperature rhythm (p < 0.01), and also with the self-reported questionnaires (p < 0.001). This suggests that ME/CFS patients exhibited modifications in circadian rhythm and hemodynamic measures, which are associated with endothelial biomarkers (ET-1 and VCAM-1). Future investigation in this area is needed to assess dysautonomia and vascular tone abnormalities, which may provide potential therapeutic targets for ME/CFS.
Assuntos
Ritmo Circadiano , Endotelina-1 , Síndrome de Fadiga Crônica , Disautonomias Primárias , Temperatura Cutânea , Adulto , Feminino , Humanos , Biomarcadores , Endotelina-1/fisiologia , Síndrome de Fadiga Crônica/fisiopatologia , Disautonomias Primárias/fisiopatologia , Molécula 1 de Adesão de Célula VascularRESUMO
The potent vasoconstrictor peptide endothelin-1 has long been recognized as a physiological regulator of vascular tone. However, pharmacological blockade of the endothelin-1 pathway has few proven indications thus far. A recent clinical trial for resistant hypertension published in The Lancet may yet herald a new era for endothelin receptor antagonists into the clinical mainstream.
Assuntos
Endotelina-1 , Hipertensão , Humanos , Endotelina-1/fisiologia , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Endotelinas/fisiologia , Antagonistas dos Receptores de Endotelina/uso terapêuticoRESUMO
Pulmonary arterial hypertension is a progressive disorder characterized by remodeling and increased small pulmonary arteries resistance. Endothelin-1 (ET-1) was related to PAH and ET-1 receptors were up-regulated selectively in the lung when exposed to toxic factor hypoxia. However, the role of ET-1 signaling in the pathogenesis of prenatal hypoxia-induced pulmonary abnormalities remains to be elucidated. Pregnant rats were divided into prenatal hypoxia (10.5 % O2 from gestational day 4-21) and control group. Their three-month-old offspring male rats were tested for vascular functions and molecular analysis, DNA methylation was assessed for cellular hypoxia. Functional testing showed that ET-1-mediated vasoconstriction was enhanced, and the expressions of endothelin A receptor/B receptor (ETAR/ETBR), inositol 1,4,5-trisphosphate receptor, type 1, and the sensitivity of calcium channels were increased in the small pulmonary arteries following prenatal hypoxia. q-PCR and DHE staining showed that the expressions of NADPH oxidase 1/4 (Nox1/4) were up-regulated, along with the increased production of superoxide anion. Furthermore, superoxide anion promoted ET-1-mediated pulmonary artery contraction. In the pulmonary artery smooth muscle cell experiments, q-PCR, Western Blot, CCK8 and DHE staining showed that the expressions of ETBR, Nox1/4, and superoxide anion were increased by hypoxia, along with promoted cell proliferation. 2,2,6,6-Tetramethyl-1-piperidinyloxy reversed hypoxia-induced cell proliferation. ETBR antagonist BQ788 inhibited hypoxia-increased expressions of Nox1/4, superoxide anion production, and proliferation of cells. Moreover, methylation analysis indicated that hypoxia decreased the methylation levels of the ETBR promoter in the pulmonary artery smooth muscle cells. The results indicated that prenatal toxic factor hypoxia resulted in abnormal ETBR activation, which enhanced ET-1-mediated vasoconstriction of pulmonary arteries and pulmonary artery smooth muscle cell proliferation through ETBR/Nox1/4-derived ROS pathway.
Assuntos
Hipóxia , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/citologia , Espécies Reativas de Oxigênio/metabolismo , Receptor de Endotelina B/metabolismo , Animais , Proliferação de Células , Metilação de DNA , Endotelina-1/fisiologia , Feminino , Hipertensão Pulmonar , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Artéria Pulmonar/fisiologia , Ratos Sprague-Dawley , Receptor de Endotelina A/genética , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/genética , VasoconstriçãoRESUMO
Diabetes elevates endothelin-1 (ET-1) in the vitreous and enhances constriction of retinal venules to this peptide. However, mechanisms contributing to ET-1-induced constriction of retinal venules are incompletely understood. We examined roles of sodium-hydrogen exchanger 1 (NHE1), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and extracellular calcium (Ca2+) in retinal venular constriction to ET-1 and the impact of diabetes on these signaling molecules. Retinal venules were isolated from control pigs and pigs with streptozocin-induced diabetes for in vitro studies. ET-1-induced vasoconstriction was abolished in the absence of extracellular Ca2+ and sensitive to c-Jun N-terminal kinase (JNK) inhibitor SP600125 but unaffected by extracellular signal-regulated kinase (ERK) inhibitor PD98059, p38 kinase inhibitor SB203580, or broad-spectrum PKC inhibitor Gö 6983. Diabetes (after 2 weeks) enhanced venular constriction to ET-1, which was insensitive to PD98059 and Gö 6983 but was prevented by NHE1 inhibitor cariporide, SB203580, and SP600125. In conclusion, extracellular Ca2+ entry and activation of JNK, independent of ERK and PKC, mediate constriction of retinal venules to ET-1. Diabetes activates p38 MAPK and NHE1, which cause enhanced venular constriction to ET-1. Treatments targeting these vascular molecules may lessen retinal complications in early diabetes.
Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Endotelina-1/farmacologia , Veia Retiniana , Trocador 1 de Sódio-Hidrogênio/fisiologia , Vasoconstrição , Animais , Cálcio/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Retinopatia Diabética/genética , Retinopatia Diabética/metabolismo , Retinopatia Diabética/fisiopatologia , Endotelina-1/sangue , Endotelina-1/fisiologia , Imidazóis/farmacologia , Masculino , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Piridinas/farmacologia , Veia Retiniana/efeitos dos fármacos , Veia Retiniana/metabolismo , Veia Retiniana/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Trocador 1 de Sódio-Hidrogênio/genética , Suínos , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/genética , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
AIM: The present study aims to investigate the antihypertensive effect and the underlying mechanism of GAO-ZI-YAO, one of the traditional Chinese medicines, in elderly spontaneous hypertensive rats (SHR). METHODS: 12-month-old male SHRs were randomly divided into five groups on the basis of treatment with different doses of GAO-ZI-YAO or angiotensin II receptor-1 blocker (ARB, Irbesartan) for four weeks. Systolic blood pressure (SBP), and serum levels of nitric oxide (NO), endothelin-1 (ET-1), angiotensin II (Ang II), vascular endothelial growth factor (VEGF), interleukin (IL)-1ß, IL-2, IL-6, and tumor necrotic factor (TNF)-α were measured. The pathological changes of ventricular muscle and thoracic aorta were observed by hematoxylin-eosin staining (H&E). RESULTS: GAO-ZI-YAO treatment reduced SBP in a dose-dependent manner accompanied by the inhibition of the development of cardiovascular remodeling. Although GAO-ZI-YAO treatment markedly increased serum levels of NO and suppressed serum levels of Ang II, this medicine did not affect the serum levels of ET-1 and VEGF. In addition, GAO-ZI-YAO also inhibited inflammatory response parameters (inflammatory cell infiltration in cardiac tissues and serum levels of IL-1ß, IL-2, IL-6, and TNF-α) in a dose-dependent manner. CONCLUSION: GAO-ZI-YAO exerts antihypertensive and anti-cardiovascular-remodeling effects in elderly SHR, which may be through regulation of NO, Ang II production, and inflammation.
Assuntos
Anti-Hipertensivos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Hipertensão/tratamento farmacológico , Medicina Tradicional Chinesa , Angiotensina II/sangue , Angiotensina II/fisiologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Citocinas/sangue , Medicamentos de Ervas Chinesas/farmacologia , Endotelina-1/sangue , Endotelina-1/fisiologia , Irbesartana/uso terapêutico , Masculino , Óxido Nítrico/sangue , Óxido Nítrico/fisiologia , Ratos , Ratos Endogâmicos SHR , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
The majority of ovarian cancer (OC) patients recur with a platinum-resistant disease. OC cells activate adaptive resistance mechanisms that are only partially described. Here we show that OC cells can adapt to chemotherapy through a positive-feedback loop that favors chemoresistance. In platinum-resistant OC cells we document that the endothelin-1 (ET-1)/endothelin A receptor axis intercepts the YAP pathway. This cross-talk occurs through the LATS/RhoA/actin-dependent pathway and contributes to prevent the chemotherapy-induced apoptosis. Mechanistically, ß-arrestin1 (ß-arr1) and YAP form a complex shaping TEAD-dependent transcriptional activity on the promoters of YAP target genes, including EDN1, which fuels a feed-forward signaling circuit that sustains a platinum-tolerant state. The FDA approved dual ET-1 receptor antagonist macitentan in co-therapy with cisplatin sensitizes resistant cells to the platinum-based therapy, reducing their metastatic potential. Furthermore, high ETAR/YAP gene expression signature is associated with a poor platinum-response in OC patients. Collectively, our findings identify in the networking between ET-1 and YAP pathways an escape strategy from chemotherapy. ET-1 receptor blockade interferes with such adaptive network and enhances platinum-induced apoptosis, representing a promising therapeutic opportunity to restore drug sensitivity in OC patients.
Assuntos
Proteínas de Ciclo Celular/fisiologia , Endotelina-1/fisiologia , Neoplasias Ovarianas/tratamento farmacológico , Fatores de Transcrição/fisiologia , Aciltransferases , Animais , Apoptose , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/patologia , Proteínas Serina-Treonina Quinases/fisiologia , Receptor de Endotelina A/fisiologia , beta-Arrestina 1/fisiologiaRESUMO
The association between plasma endothelin-1 (ET-1) and obesity has been documented for decades, yet the contribution of ET-1 to risk factors associated with obesity is not fully understood. In 1994, one of first papers to document this association also noted a positive correlation between plasma insulin and ET-1, suggesting a potential contribution of ET-1 to the development of insulin resistance. Both endogenous receptors for ET-1, ETA and ETB are present in all insulin-sensitive tissues including adipose, liver and muscle, and ET-1 actions within these tissues suggest that ET-1 may be playing a role in the pathogenesis of insulin resistance. Further, antagonists for ET-1 receptors are clinically approved making these sites attractive therapeutic targets. This review focuses on known mechanisms through which ET-1 affects plasma lipid profiles and insulin signalling in these metabolically important tissues and also identifies gaps in our understanding of ET-1 in obesity-related pathophysiology.
Assuntos
Endotelina-1 , Resistência à Insulina , Obesidade/fisiopatologia , Endotelina-1/fisiologia , Humanos , Receptor de Endotelina A/fisiologiaRESUMO
GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in the heart, liver, and kidney, but roles in nonadipose tissues are poorly defined. GPR81 agonists, developed to improve blood lipid profile, might also provide insights into GPR81 physiology. Here, we assessed the blood pressure and renal hemodynamic responses to the GPR81 agonist, AZ'5538. In male wild-type mice, intravenous AZ'5538 infusion caused a rapid and sustained increase in systolic and diastolic blood pressure. Renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate were all significantly reduced. AZ'5538 had no effect on blood pressure or renal hemodynamics in Gpr81-/- mice. Gpr81 mRNA was expressed in renal artery vascular smooth muscle, in the afferent arteriole, in glomerular and medullary perivascular cells, and in pericyte-like cells isolated from kidney. Intravenous AZ'5538 increased plasma ET-1 (endothelin 1), and pretreatment with BQ123 (endothelin-A receptor antagonist) prevented the pressor effects of GPR81 activation, whereas BQ788 (endothelin-B receptor antagonist) did not. Renal ischemia-reperfusion injury, which increases renal extracellular lactate, increased the renal expression of genes encoding ET-1, KIM-1 (Kidney Injury Molecule 1), collagen type 1-α1, TNF-α (tumor necrosis factor-α), and F4/80 in wild-type mice but not in Gpr81-/- mice. In summary, activation of GPR81 in vascular smooth muscle and perivascular cells regulates renal hemodynamics, mediated by release of the potent vasoconstrictor ET-1. This suggests that lactate may be a paracrine regulator of renal blood flow, particularly relevant when extracellular lactate is high as occurs during ischemic renal disease.
Assuntos
Endotelina-1/fisiologia , Hemodinâmica/efeitos dos fármacos , Receptores Acoplados a Proteínas G/agonistas , Animais , Artérias/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Bosentana/farmacologia , Endotelina-1/sangue , Taxa de Filtração Glomerular/efeitos dos fármacos , Coração/efeitos dos fármacos , Hemodinâmica/fisiologia , Infusões Intravenosas , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Lactatos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Oligopeptídeos/farmacologia , Comunicação Parácrina , Peptídeos Cíclicos/farmacologia , Pericitos/efeitos dos fármacos , Pericitos/metabolismo , Piperidinas/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiologia , Circulação Renal/efeitos dos fármacos , Circulação Renal/fisiologia , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/fisiopatologiaRESUMO
KEY POINTS: Exercise in patients with hypertension can be accompanied by an abnormal cardiovascular response that includes attenuated blood flow and an augmented pressor response. Endothelin-1, a very potent vasoconstrictor, is a key modulator of blood flow and pressure during in health and has been implicated as a potential cause of the dysfunction in hypertension. We assessed the role of endothelin-1, acting through endothelin A (ETA ) receptors, in modulating the central and peripheral cardiovascular responses to exercise in patients with hypertension via local antagonism of these receptors during exercise. ETA receptor antagonism markedly increased leg blood flow, vascular conductance, oxygen delivery, and oxygen consumption during exercise; interestingly, these changes occurred in the presence of reduced leg perfusion pressure, indicating that these augmentations were driven by changes in vascular resistance. These data indicate that ETA receptor antagonism could be a viable therapeutic approach to improve blood flow during exercise in hypertension. ABSTRACT: Patients with hypertension can exhibit impaired muscle blood flow and exaggerated increases in blood pressure during exercise. While endothelin (ET)-1 plays a role in regulating blood flow and pressure during exercise in health, little is known about the role of ET-1 in the cardiovascular response to exercise in hypertension. Therefore, eight volunteers diagnosed with hypertension were studied during exercise with either saline or BQ-123 (ETA receptor antagonist) infusion following a 2-week withdrawal of anti-hypertensive medications. The common femoral artery and vein were catheterized for drug infusion, blood collection and blood pressure measurements, and leg blood flow was measured by Doppler ultrasound. Patients exercised at both absolute (0, 5, 10, 15 W) and relative (40, 60, 80% peak power) intensities. BQ-123 increased blood flow at rest (79 ± 87 ml/min; P = 0.03) and augmented the exercise-induced hyperaemia at most intensities (80% saline: Δ3818±1222 vs. BQ-123: Δ4812±1469 ml/min; P = 0.001). BQ-123 reduced leg MAP at rest (-8 ± 4 mmHg; P < 0.001) and lower intensities (0-10 W; P < 0.05). Systemic diastolic blood pressure was reduced (0 W, 40%; P < 0.05), but systemic MAP was defended by an increased cardiac output. The exercise pressor response (ΔMAP) did not differ between conditions (80% saline: 25 ± 10, BQ-123: 30 ± 7 mmHg; P = 0.17). Thus, ET-1, acting through the ETA receptors, contributes to the control of blood pressure at rest and lower intensity exercise in these patients. Furthermore, the finding that ET-1 constrains the blood flow response to exercise suggests that ETA receptor antagonism could be a therapeutic approach to improve blood flow during exercise in hypertension.
Assuntos
Exercício Físico , Hipertensão/fisiopatologia , Músculo Esquelético/irrigação sanguínea , Receptor de Endotelina A/fisiologia , Fluxo Sanguíneo Regional , Pressão Sanguínea , Antagonistas dos Receptores de Endotelina/farmacologia , Endotelina-1/fisiologia , Humanos , Peptídeos Cíclicos/farmacologiaRESUMO
BACKGROUND AND AIMS: Endothelin-1 (ET-1) and arginase are both suggested to be involved in the inflammatory processes and development of endothelial dysfunction in atherosclerosis. However, information regarding the roles of ET-1 and arginase, as well as the interactions between the two in human atherosclerosis, is scarce. We investigated the expression of ET-1 and its receptors, ETA and ETB, as well as arginase in human carotid atherosclerotic plaques and determined the functional interactions between ET-1 and arginase in endothelial cells and THP-1-derived macrophages. METHODS: Carotid plaques and blood samples were retreived from patients undergoing surgery for symptomatic or asymptomatic carotid stenosis. Plaque gene and protein expression was determined and related to clinical characteristics. Functional interactions between ET-1 and arginase were investigated in endothelial cells and THP-1â¯cells. RESULTS: Expression of ET-1 and ETB receptors was increased in plaques from patients with symptomatic carotid artery disease. ET-1 was co-localized with arginase 1 and arginase 2 in the necrotic core, together with macrophage markers CD163 and CD68. Arginase 2, ET-1 and ETB receptors were expressed in endothelial cells as well as in smooth muscle cells in the fibrous cap. ET-1 increased arginase 2 mRNA expression and arginase activity in endothelial cells and arginase activity in macrophages. Moreover, ET-1 stimulated formation of reactive oxygen species (ROS) in THP-1-derived macrophages via an arginase-dependent mechanism. CONCLUSIONS: This is the first study that demonstrates co-localization of ET-1 and arginase 2 in human atherosclerotic plaques. ET-1 stimulated arginase 2 expression and activity in endothelial cells, as well as arginase activity and ROS formation in macrophages via an arginase-dependent mechanism. These results indicate an important interaction between the ET pathway and arginase in human atherosclerotic plaques.
Assuntos
Arginase/fisiologia , Endotelina-1/fisiologia , Placa Aterosclerótica/metabolismo , Receptor de Endotelina B/fisiologia , Arginase/biossíntese , Células Cultivadas , Células Endoteliais , Endotelina-1/biossíntese , HumanosRESUMO
Hyperlipidemia and oxidative stress are indispensable features of chronic kidney disease (CKD) that favor the development of atherogenic plaques and cardiovascular disease (CVD). A number of vasoactive mediators including proprotein convertase subtilisin-kexin type 9 (PCSK9), endothelin-1, nitric oxide, and angiotensin II have fundamental roles in the pathophysiology of atherosclerotic events; moreover, their levels are affected by dyslipidemia and oxidative stress due to renal dysfunction. Therefore, therapeutic measures aimed at correcting dyslipidemia and alleviating oxidative stress could potentially protect against CVD in CKD patients. In this review, we discuss the relation between dyslipidemia, oxidative stress, and vasoactive mediators as well as the available treatment options against these disturbances in CKD patients.
Assuntos
Angiotensina II/fisiologia , Dislipidemias/complicações , Dislipidemias/metabolismo , Endotelina-1/fisiologia , Óxido Nítrico/fisiologia , Estresse Oxidativo , Pró-Proteína Convertase 9/fisiologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , HumanosAssuntos
Doenças Cardiovasculares/genética , Doença das Coronárias/genética , Endotelina-1/fisiologia , Proteínas dos Microfilamentos/fisiologia , Doenças Cardiovasculares/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Doença das Coronárias/epidemiologia , Suscetibilidade a Doenças , Endotelina-1/biossíntese , Endotelina-1/genética , Feminino , Displasia Fibromuscular/complicações , Displasia Fibromuscular/genética , Regulação da Expressão Gênica , Humanos , Proteínas dos Microfilamentos/biossíntese , Proteínas dos Microfilamentos/genética , Infarto do Miocárdio/etiologia , Polimorfismo de Nucleotídeo Único , Distribuição por SexoRESUMO
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/químicaRESUMO
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/secundárioRESUMO
AIMS: Hypertension is common. Recent data suggest that macrophages (Mφ) contribute to, and protect from, hypertension. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor with additional pro-inflammatory properties. We investigated the role of the ET system in experimental and clinical hypertension by modifying Mφ number and phenotype. METHODS AND RESULTS: In vitro, Mφ ET receptor function was explored using pharmacological, gene silencing, and knockout approaches. Using the CD11b-DTR mouse and novel mice with myeloid cell-specific endothelin-B (ETB) receptor deficiency (LysMETB-/-), we explored the effects of modifying Mφ number and phenotype on the hypertensive effects of ET-1, angiotensin II (ANG II), a model that is ET-1 dependent, and salt. In patients with small vessel vasculitis, the impacts of Mφ depleting and non-depleting therapies on blood pressure (BP) and endothelial function were examined. Mouse and human Mφ expressed both endothelin-A and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of Mφ with exogenous ET-1 did not polarize Mφ phenotype. Interestingly, both mouse and human Mφ cleared ET-1 through ETB receptor mediated, and dynamin-dependent, endocytosis. Mφ depletion resulted in an augmented chronic hypertensive response to both ET-1 and salt. LysMETB-/- mice displayed an exaggerated hypertensive response to both ET-1 and ANG II. Finally, in patients who received Mφ depleting immunotherapy BP was higher and endothelial function worse than in those receiving non-depleting therapies. CONCLUSION: Mφ and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension.
Assuntos
Angiotensina II/fisiologia , Endotelina-1/fisiologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Macrófagos/fisiologia , Receptor de Endotelina B/fisiologia , Animais , Modelos Animais de Doenças , Endocitose/fisiologia , Humanos , Hipertensão/etiologia , Camundongos , Receptor de Endotelina ARESUMO
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/fisiologiaRESUMO
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/fisiologiaRESUMO
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 TireoideRESUMO
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.