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1
Chen, Chih-Ying, Low-Tone Ho, Feng-Yuan Yang, Chi-Chang Juan, and Lo-Chun Au. "Prunellae Spica Extract Contains Antagonists for Human Endothelin Receptors." American Journal of Chinese Medicine 41, no. 01 (January 2013): 85–98. http://dx.doi.org/10.1142/s0192415x13500079.
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Endothelin-1 (ET-1) is a powerful vasoconstrictor that contributes to blood pressure elevation. The biological effects of ETs are mediated by two receptors, namely, endothelin type A receptor (ETAR) and endothelin type B receptor (ETBR). Chinese herbal medicines (CHM) with antagonist activity for these two receptors were screened by establishing stable clones of CHO-K1 cells expressing high levels of human ETAR and ETBR, namely CHO-ETAR and CHO-ETBR.The aqueous extract of Prunellae Spica (P1) inhibited the binding of 125I-ET-1 to ETAR and ETBR in CHO-ETAR and CHO-ETBR cells, respectively. P1 suppressed the ET-1-induced mobilization of intracellular Ca2+ . Through the alcohol fractionation of P1, the antagonists of human ETAR and ETBR were found to belong to different, separable ingredients and the antagonist of ETAR is more soluble in alcohol. The two antagonists were also effective in the test on human primary cells, HASMC and HUVEC. P1 successfully prevented the development of ET-1-associated hypertension in rats without further purification. These results indicate the presence of anti-hypertensive ingredients in P. Spica extract, at least through the inactivation of ETAR and/or ETBR.
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DEL BUFALO, Donatella, Valeriana DI CASTRO, Annamaria BIROCCIO, Debora SALANI, Laura ROSANÒ, Francesca SPINELLA, and Anna BAGNATO. "Endothelin-1 acts as a survival factor in ovarian carcinoma cells." Clinical Science 103, s2002 (September 1, 2002): 302S—305S. http://dx.doi.org/10.1042/cs103s302s.
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The aim of this study was to evaluate the role of endothelin-1 (ET-1) in the sensitivity of ovarian carcinoma to paclitaxel, one of the most common drugs used for the management of this tumour histotype. ET-1 is a powerful mitogenic peptide produced by ovarian carcinomas and it acts as an autocrine growth factor, selectively through ETA receptor (ETAR), which is predominantly expressed in this tumour. OVCA 433 and HEY, two ovarian carcinoma cell lines, which produce elevated amounts of ET-1 and express abundantly high-affinity ETARs, were used. As demonstrated by sub-G1 peak in DNA content histograms and terminal transferase deoxytidyl uridine end labelling assay, we found that paclitaxel induces cytotoxic effect through the activation of apoptosis in both cell lines. When the treatment with paclitaxel was performed in association with ET-1, paclitaxel-induced apoptosis was inhibited. In order to evaluate which ET-1 receptor mediated the effect of ET-1 on protection from paclitaxel-induced apoptosis, we performed experiments using two selective antagonists for ETAR (BQ-123) and for ETBR (BQ-788). We showed that ETAR blockade inhibits the ET-1-induced survival activity against paclitaxel-mediated apoptosis. However, no effect was observed on blocking ETBR with BQ-788. Our results establish a novel role for ET-1 in determining survival of ovarian carcinoma cells and suggest that pharmacological ETAR blockade using a specific ETAR antagonist may provide a novel approach to the treatment of ovarian carcinoma in combination therapy.
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Al Lafi, Sawsan M., Shushan B. Artinian, Suzan S. Boutary, Nadine S. Zwainy, Khalil M. Bitar, and Anwar B. Bikhazi. "Aliskiren, exendin-4, and insulin: their impact on endothelin receptor subtype(s) regulation/binding in type 1 diabetic rat hearts." Canadian Journal of Physiology and Pharmacology 91, no. 10 (October 2013): 830–38. http://dx.doi.org/10.1139/cjpp-2013-0095.
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This study focuses on the impact of aliskiren and (or) glucagon-like peptide-1 analogue on the binding affinity/regulation of endothelin-1 (ET-1) to its receptor subtypes A (ETAR) and B (ETBR) at the level of the coronary endothelium and the cardiomyocytes in a type-1 diabetic rat model. Seven groups were used: (i) normal rats, (ii) rats with induced diabetes, (iii) rats with induced diabetes that were treated with insulin, (iv) rats with induced diabetes that were treated with exendin-4, (v) rats with induced diabetes that were treated with aliskiren, (vi) rats with induced diabetes that were co-treated with insulin plus aliskiren, and (vii) rats with induced diabetes that were co-treated with exendin-4 plus aliskiren. Heart perfusion with [125I]-ET-1 was employed to estimate ET-1 binding affinity (τ = 1/K–n) to ETAR and ETBR at the level of the coronary endothelium and the cardiomyocytes. Plasma ET-1 levels were measured using enzyme immunoassay, whereas densities of ETAR and ETBR were detected using Western blot. No significance differences were detected in the τ of ETAR and ETBR between normal and diabetic in cardiomyocytes and the coronary endothelium. Exendin-4 normalized the τ value for ETAR and ETBR on coronary endothelium, while aliskiren normalized it on cardiomyocytes. Furthermore, ETAR and ETBR densities were normalized with monotreatments of aliskiren and exendin-4, compared with up-regulated ETAR and down-regulated ETBR band densities in the diabetic animals. Our data indicate that aliskiren alleviates diabetes-associated hypertrophy in type 1 diabetes mellitus.
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Zhao, Yumin, Zhisheng Dang, Shuo Xu, and Shigui Chong. "Heat shock protein 47 effects on hepatic stellate cell-associated receptors in hepatic fibrosis of Schistosoma japonicum-infected mice." Biological Chemistry 398, no. 12 (November 27, 2017): 1357–66. http://dx.doi.org/10.1515/hsz-2017-0177.
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AbstractThe study aimed to explore the regulation of heat shock protein 47 (HSP47) on expressions of receptors associated with hepatic stellate cell (HSC) in liver fibrosis mouse models induced bySchistosoma japonicum(S. japonicum). Mouse fibroblasts (NIH/3T3) were transfected with HSP47 shRNA plasmid by lipofectamine transfection, and experimental fibrosis in HSCs was studied inS. japonicummouse models treated with HSP47 shRNAin vivo. HSP47 expression was assessed using Western blot and real-time PCR. Flow cytometry was adopted to determine the expression of cell membrane receptors. HSP47-shRNA could markedly down-regulate the expression of collagen (Col1a1 and Col3a1). The expressions of HSP47, endothelin receptor A (ETAR) and endothelin receptor B (ETBR) significantly increased in the liver tissue of infected mice. However, the expressions of ETAR and HSP47 and ETBR remarkably decreased after the administration of HSP47 shRNAin vitroandin vivo. ETAR and ETBR levels were found to be positively correlated with HSP47 expression. HSP47 might exert influence on liver fibrosis via the regulation of ETAR and ETBR.
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Teng, Fang, Ling Wang, Kavindra V. Singh, Barbara E. Murray, and George M. Weinstock. "Involvement of PhoP-PhoS Homologs in Enterococcus faecalis Virulence." Infection and Immunity 70, no. 4 (April 2002): 1991–96. http://dx.doi.org/10.1128/iai.70.4.1991-1996.2002.
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ABSTRACT Eleven PhoP-PhoS homolog pairs were identified by searching the Enterococcus faecalis V583 genome sequence database at The Institute for Genomic Research with the Bacillus subtilis PhoP-PhoS sequences. Each pair appears to be a potential two-component system composed of a response regulator and a sensor kinase. Seven of the homologs were disrupted in E. faecalis strain OG1RF. TX10293, a mutant disrupted in one of these genes (etaR, the first gene of the gene pair designated etaRS), showed delayed killing and a higher 50% lethal dose in a mouse peritonitis model. The predicted EtaR protein sequence showed greatest similarity to LisR of Listeria monocytogenes (77%) and CsrR of Streptococcus pyogenes (70%); EtaS is 53% similar to LisK and 54% similar to CsrS. When grown in vitro, the TX10293 mutant was more sensitive to low pH (pH 3.4) and more resistant to high temperature (55°C) than wild-type OG1RF. In conclusion, many potential two-component systems are identified for E. faecalis, one of which, EtaRS, was shown to be involved in stress response and virulence.
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Fellner, Susan K., and William Arendshorst. "Endothelin-A and -B receptors, superoxide, and Ca2+ signaling in afferent arterioles." American Journal of Physiology-Renal Physiology 292, no. 1 (January 2007): F175—F184. http://dx.doi.org/10.1152/ajprenal.00050.2006.
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It is unknown if endothelin-A and -B receptors (ETAR and ETBR) activate the production of superoxide via NAD(P)H oxidase and subsequently stimulate the formation of cyclic adenine diphosphate ribose (cADPR) in afferent arterioles. Vessels were isolated from rat kidney and loaded with fura 2. Endothelin-1 (ET-1) rapidly increased cytosolic Ca2+ concentration ([Ca2+]i) by 303 nM. The superoxide dismutase mimetic tempol, the NAD(P)H oxidase inhibitor apocynin, and nicotinamide, an inhibitor of ADPR cyclase, diminished the response by ∼60%. The ETBR agonist sarafotoxin 6c (S6c) increased peak [Ca2+]i by 117 nM. Subsequent addition of ET-1 in the continued presence of S6c caused an additional [Ca2+]i peak of 225 nM. Neither nicotinamide or 8-bromo- (8-Br) cADPR nor apocynin decreased the [Ca2+]i response to S6c, but inhibited the subsequent [Ca2+]i response to ET-1. The ETBR blockers BQ-788 and A-192621 prevented the S6c [Ca2+]i peak and reduced the ET-1 response by more than one-half, suggesting an ETBR/ETAR interaction. In contrast, the ETAR blocker BQ-123 had no effect on the S6c [Ca2+]i peak and obliterated the subsequent ET-1 response. ET-1 immediately stimulated superoxide formation (measured with TEMPO-9-AC, 68 arbitrary units) that was inhibited 95% by apocynin or diphenyl iodonium. S6c or IRL-1620 increased superoxide by 8% of that caused by subsequent ET-1 addition. We conclude that ETAR activation of afferent arterioles increases the formation of superoxide that accounts for ∼60% of subsequent Ca2+ signaling. ETBR activation appears to result in only minor increases in superoxide production. Nicotinamide and 8-Br-cADPR results suggest that ET-1 (and primarily ETAR) causes the activation of vascular smooth muscle cell-ADPR cyclase.
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VENUTI, Aldo, Debora SALANI, Alessia CIRILLI, Paola SIMEONE, Antonio MULLER, Silvio FLAMINI, Robert PADLEY, and Anna BAGNATO. "Endothelin receptor blockade inhibits the growth of human papillomavirus-associated cervical carcinoma." Clinical Science 103, s2002 (September 1, 2002): 310S—313S. http://dx.doi.org/10.1042/cs103s310s.
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Human papillomaviruses (HPVs) are associated with cervical cancer and interact with growth factors that may enhance malignant transformation of cervical carcinoma cells. Endothelin-1 (ET-1) is released from HPV-transfected keratinocytes and induces increased growth response in these cell lines in comparison with normal cells. HPV-positive cancer cells secrete ET-1 and express mRNA for ET-1 and its receptors, whereas HPV-negative carcinoma cell lines express only the ETB receptor (ETBR) mRNA and do not secrete ET-1. In HPV-positive cancer cells, ETAR mediates the ET-1-induced mitogenic effect and sustains the basal growth rate of unstimulated cervical tumour cells. Therefore, ET-1 may be involved in the neoplastic growth of HPV-associated cervical carcinoma, where the increased ET-1 autocrine loop can be targeted for antitumour therapy. In the present work, the action of specific antagonists of ETAR (BQ-123 and ABT-627), was analysed in CaSki and C33A cells that are derived from human cervical carcinoma. CaSki cells are HPV-16-positive, produce ET-1 and posses ETAR and ETBR, whereas the C33A line is HPV-negative, does not secrete ET-1 and has no ETAR. In HPV-positive cancer cells ABT-627 strongly inhibited the proliferation induced by ET-1 and substantially reduced the basal growth rate of unstimulated cervical tumour cells, whereas the ETBR antagonist had no effect. These results demonstrate that ET-1 participates in the progression of neoplastic growth in HPV-associated carcinoma, in which ETAR expression is increased and could be targeted for antitumour therapy. In conclusion, an ET-1 autocrine loop is involved in tumour cell proliferation via ETAR, and ABT-627 is effective in controlling proliferation of cervical carcinoma cells.
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Bagnato, Anna, Francesca Spinella, and Laura Rosanò. "Emerging role of the endothelin axis in ovarian tumor progression." Endocrine-Related Cancer 12, no. 4 (December 2005): 761–72. http://dx.doi.org/10.1677/erc.1.01077.
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Ovarian cancer is the leading cause of gynecologic cancer-related deaths. The endothelin (ET) axis, which includes ET-1, ET-2, ET-3, and the ET receptors, ETAR and ETBR, represents a novel target in tumor treatment. ET-1 may directly contribute to tumor growth and indirectly modulate tumor–host interactions in various tumors such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast carcinoma, Kaposi’s sarcoma, brain tumors and melanoma. Extensive experimental evidence links ETAR overexpression with tumor progression in ovarian cancer. ETAR engagement can in fact activate multiple signal transduction pathways including protein kinase C, phosphati-dylinositol 3-kinase, mitogen-activated protein kinase and transactivate epidermal growth factor receptor, which play a role in ovarian tumor growth and invasion. The effects of ETAR signaling are wide ranging and involve both cancer cells and their surrounding stroma, including the vasculature. Upon being activated, the ETAR mediates multiple tumor-promoting activities, including enhanced cell proliferation, escape from apoptosis, angiogenesis, epithelial–mesenchymal transition and increased motility and invasiveness. These findings indicate that activation of ETAR by ET-1 is a key mechanism in the cellular signaling network promoting ovarian cancer growth and progression. The predominant role played by ETAR in cancer has led to the development of small molecules that antagonize the binding of ET-1 to ETAR. The emerging preclinical data presented here provide a rationale for the clinical evaluation of these molecules in which targeting the related signaling cascade via ETAR blockade may be advantageous in the treatment of advanced stage ovarian carcinoma.
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Kopp, Ulla C., Michael Z. Cicha, and Lori A. Smith. "Differential effects of endothelin on activation of renal mechanosensory nerves: stimulatory in high-sodium diet and inhibitory in low-sodium diet." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 5 (November 2006): R1545—R1556. http://dx.doi.org/10.1152/ajpregu.00878.2005.
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Activation of renal mechanosensory nerves is enhanced by high and suppressed by low sodium dietary intake. Afferent renal denervation results in salt-sensitive hypertension, suggesting that activation of the afferent renal nerves contributes to water and sodium balance. Another model of salt-sensitive hypertension is the endothelin B receptor (ETBR)-deficient rat. ET and its receptors are present in sensory nerves. Therefore, we examined whether ET receptor blockade altered the responsiveness of the renal sensory nerves. In anesthetized rats fed high-sodium diet, renal pelvic administration of the ETBR antagonist BQ-788 reduced the afferent renal nerve activity (ARNA) response to increasing renal pelvic pressure 7.5 mmHg from 26 ± 3 to 9 ± 3% and the PGE2-mediated renal pelvic release of substance P from 9 ± 1 to 3 ± 1 pg/min. Conversely, in rats fed low-sodium diet, renal pelvic administration of the ETAR antagonist BQ-123 enhanced the ARNA response to increased renal pelvic pressure from 9 ± 2 to 23 ± 6% and the PGE2-mediated renal pelvic release of substance P from 0 ± 0 to 6 ± 1 pg/min. Adding the ETAR antagonist to ETBR-blocked renal pelvises restored the responsiveness of renal sensory nerves in rats fed a high-sodium diet. Adding the ETBR antagonist to ETAR-blocked pelvises suppressed the responsiveness of the renal sensory nerves in rats fed a low-sodium diet. In conclusion, activation of ETBR and ETAR contributes to the enhanced and suppressed responsiveness of renal sensory nerves in conditions of high- and low-sodium dietary intake, respectively. Impaired renorenal reflexes may contribute to the salt-sensitive hypertension in the ETBR-deficient rat.
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Sun, Yuan, Xicheng Zhang, Zhaolei Chen, Miao Xu, and Minghui Ou. "Reduction of Uterine Perfusion Pressure Induced Redistribution of Endothelin Receptor Type-B Between the Intima and Media Contributes to the Pathogenesis of Pregnancy-Induced Hypertension." Cellular Physiology and Biochemistry 44, no. 5 (2017): 1715–25. http://dx.doi.org/10.1159/000485777.
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Background/Aims: Studies have shown that a change in endothelin receptor expression in the artery is related to pregnancy-induced hypertension (PIH). However, the mechanism underlying this change remains unclear. Methods: To test whether the distribution of endothelin receptor type-A (ETAR) and type-B (ETBR) plays an important role in PIH, a reduction of uterine perfusion pressure (RUPP) rat model was used to mimic some of the features of PIH; the resulting variable endothelin receptor expression was investigated in the media and intima of the aorta. Single vascular smooth muscle cells (VSMCs) were isolated from RUPP and normal pregnant (NP) rats to study the effect of ETAR and ETBR in smooth muscle cells. Results: Compared with NP rats, RUPP rats had a significant redistribution of ETBR expression in the intima and media, while there was no significant difference in ETAR expression between the two groups. ETBR upregulation in VSMCs enhanced cellular contraction and contributed to PIH. The TNF-α plasma levels in RUPP rats were two-fold higher than those of NP rats, which upregulated the expression of ETBR in VSMCS through the NF-κB pathways in RUPP rats. Conclusion: Redistribution of ETBR between the media and intima played an important role in the pathogenesis of PIH.
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Cook, N., R. Brais, W. Qian, C. Chan Wah Hak, and P. G. Corrie. "Endothelin-1 and endothelin B receptor expression in pancreatic adenocarcinoma." Journal of Clinical Pathology 68, no. 4 (January 8, 2015): 309–13. http://dx.doi.org/10.1136/jclinpath-2014-202521.
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BackgroundEndothelin-1 (ET-1) acting through endothelin A and B receptors (ETAR and ETBR) has been implicated in the development of cancer. The endothelin axis has not previously been characterised in human pancreatic adenocarcinoma (PAC).MethodsExpression of ET-1, ETAR, ETBR, vascular endothelial growth factor and microvessel density (MVD) was determined by immunohistochemistry in 45 surgically resected human PACs and 15 non-cancer human pancreas samples.ResultsPAC had the highest staining intensity for ET-1 and ETBR: 38% PAC samples scored 2+ or more compared with 7% non-cancer sample in ET-1; 58% PAC samples scored 2+ compared with 0% non-cancer samples in ETBR. MVD was significantly lower in PAC compared with non-cancer tissue (p<0.0001).ConclusionsPAC was characterised by greater expression of ET-1 and ETBR compared with normal pancreas.
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Kern, Jan, Viola Maass, Jan Rupp, and Matthias Maass. "Proliferative stimulation of the vascular endothelin-1 axis in vitro and ex vivo by infection with Chlamydia pneumoniae." Thrombosis and Haemostasis 102, no. 10 (2009): 743–53. http://dx.doi.org/10.1160/th09-02-0128.
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SummaryEndothelin-1 (ET-1) is a vasoactive peptide that modifies vascular function via the G-protein coupled transmembrane receptors, Endothelin-A receptor (ETAR) and Endothelin-B receptor (ETBR). Dysregulation of the ET-1 axis plays a role in atherosclerotic development as it triggers cell proliferation, inflammation, and vasoconstriction.The respiratory pathogen Chlamydia pneumoniae (Cp) has been recovered from atherosclerotic lesions, and related to atherogenesis, via activation of vascular small GTPases and leukocyte recruitment. Cp effectively reprograms host cell signalling and is able to enter an intracellular persistent state in vascular cells that is refractory to antibiotics. Upon chlamydial infection, vascular smooth muscle cells, which do not produce significant ET-1 under physiological conditions were switched into a fundamental source of ET-1 mRNA and protein in a p38-MAP-kinase-dependent pathway. Endothelial cells did not overproduce ET-1 but showed upregulation of mitogenic ETAR mRNA and protein while the counterbalancing ETBR, which regulates ET-1 clearance, remained unaffected.This disruption of the ET-1 axis was confirmed in an ex vivo mouse aortic ring model, and resulted in endothelial cell proliferation that could be abrogated by ETAR-siRNA and the selective ETAR-antagonist BQ-123. Chronic chlamydial infection of the vascular wall might represent a permanent noxious stimulus linked to the endothelial cell proliferation characteristic of early atherosclerosis. Suppression of this deleterious paracrine loop by ETAR antagonism opens up a new option of preventing possible vascular sequelae of otherwise untreatable chronic chlamydial infection. In conclusion, this is the first study to demonstrate infection to dysregulate the ET-1 axis towards inducing a proatherogenic proliferative phenotype.
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Rademacher, Judith, Angela Kill, Kathrin Mattat, Duska Dragun, Elise Siegert, Jeannine Günther, and Gabriela Riemekasten. "Monocytic Angiotensin and Endothelin Receptor Imbalance Modulate Secretion of the Profibrotic Chemokine Ligand 18." Journal of Rheumatology 43, no. 3 (January 15, 2016): 587–91. http://dx.doi.org/10.3899/jrheum.150474.
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Objective.To assess monocytic expression and ratio of angiotensin and endothelin receptors in systemic sclerosis (SSc) and their functional relevance.Methods.Receptor expression was measured by flow cytometry. Chemokine ligand 18 (CCL18) concentration in supernatants of peripheral blood mononuclear cells stimulated with immunoglobulin G was measured by ELISA.Results.Monocytes of patients with SSc presented an increased angiotensin II Type 1 receptor (AT1R)/AT2R ratio compared with those of healthy donors. Patients with lung fibrosis and patients with high modified Rodnan skin score showed a reduced endothelin 1 Type A receptor (ETAR)/ETBR ratio. High AT1R/AT2R, but low ETAR/ETBR ratios corresponded to higher CCL18 secretion.Conclusion.Altered angiotensin and endothelin receptor ratios observed in SSc influence autoantibody-mediated effects such as secretion of profibrotic CCL18.
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Herrmann, E., S. Bierer, M. Boegemann, E. Eltze, L. Hertle, and C. Wülfing. "Expression of the endothelin axis and microvessel density in bladder cancer." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 4583. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.4583.
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4583 Background: Endothelin-1 (ET-1) and its receptors ETAR and ETBR, referred to as the Endothelin (ET)-axis play an emerging role in cancer. The ET-axis has been shown to be involved in proliferation, angiogenesis and metastasis. We investigated the effect of the ET-axis on microvessel density (MVD) and on the clinical prognosis in patients with invasive carcinoma of the bladder. Methods: Archival tumor tissue of 157 consecutive patients was reviewed and representing tumor blocks were selected. Paraffin sections were assessed immunhistochemically using mono- and polyclonal antibodies for ET-1, ETAR,ETBR and CD34 (MVD). Staining intensities were analyzed semiquantitatively and the MVD was calculated as vessels per field. The results were correlated with various pathological and clinical factors, as well as with disease-free and overall survival. Results: Overexpression of ET-1, ETAR and ETBR was identified in 26.8%, 58.8% and 76.9% of cases, respectively. Normal urothelium was constantly negative. No association with TNM staging and histologic grading was found. However, patients with ETBR expression tended to have organ-confined tumors (P = 0.16) and no vascular invasion (P = 0.09), the latter being statistically significant in the subgroup of G3 tumors (P = 0.02). T1 and T2 (MVD = 32,2) tumors had greater MVD compared to T3 and T4 tumors (MVD = 21,2) (P = 0.02), showing an association of MVD and overexpression of ET-1 (P = 0.027). ETBR-positive tumors were associated with favorable disease-free survival (P = 0.04). In urothelial carcinomas the MVD was 23,7, whereas squamous cell carcinomas had a MVD of 17,8 (P = 0.04). Conclusion: The ET-axis is overexpressed in invasive bladder cancer. Urothelial carcinomas are significantly greater vascularized compared to squamous cell carcinomas. Organ-confined tumors showed more MVD than T3 and T4 tumors, which is related to ET-1 expression in this subgroup. ETBR appears to predominate in bladder cancer and is associated with a more favorable prognosis. No significant financial relationships to disclose.
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Li, Long, Mushuang Hu, Long Zheng, Chao Zhang, Jiawei Li, Ruiming Rong, Tongyu Zhu, and Yichen Jia. "Endothelin Receptor Down-Regulation Mediated Ligand Regulation Mechanisms Protect Against Cellular Hypoxia Injury in Rat Vascular Endothelial Cells." Cellular Physiology and Biochemistry 40, no. 6 (2016): 1443–54. http://dx.doi.org/10.1159/000453196.
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Objective: Investigation of the effect of endothelin receptor A (ETaR)-targeting small interfering RNA (siRNA) on rat vascular endothelial cellular hypoxia injury, as well as its underlying mechanism. Methods: An in vitro rat vascular smooth muscle cells - endothelial cells co-culture model was established and transfected with ETaR siRNA before hypoxia treatment. Cell culture supernatant, cellular protein and RNA were collected and examined at 0.5hrs, 1hrs, 2hrs, 4hrs, 8hrs, 16hrs, 24hrs and 48hrs of hypoxia with 1% oxygen. The time point at which the best silencing effect was achieved was chosen, eNOS inhibitor L-NAME was added, and post hypoxia cell culture supernatant, cellular protein and RNA was collected for further examination. Results: After hypoxic treatment, endothelial-1 (ET-1) and ETaR expression levels gradually increased as oxygen deprivation extended. ET-1 and ETaR expression levels were significantly lower in the ETaR siRNA group compared with the Hypoxia group (P<0.001). Such difference peaked at 4hrs of hypoxia. ELISA examination of cell culture supernatant revealed that the amount of ET-1 and TGF-βin the ETaR siRNA group were significantly lower compared to the Hypoxia group at all times, while the amount of NO and eNOS was higher. After 4 hrs of hypoxia, Smad2, Smad3, HIF-1, TNF-α, IFN-γ, IL-6, MCP-1, NF-κb, ET-1 and ANG II mRNA expression in endothelial cells and ETaR mRNA expression in A-10 cells of the ETaR siRNA group were lower than those of the Hypoxia siRNA group, while such results were much higher in the L-NAME group. Western Blot results showed lower expression of ETaR in the ETaR siRNA group compared with the hypoxia and negative siRNA groups, as well as significantly higher ETaR expression in the L-NAME group compared with the ETaR siRNA group. PI3K and p-AKT expression levels were mildly elevated after mild oxygen deprivation, and ETaR siRNA was able to enhance such elevation induced by hypoxia. In the L-NAME group, PI3K and p-AKT expression was much higher than the ETaR siRNA group. PKG and sGC expression levels significantly descended after mild oxygen deprivation. While such levels were higher in the ETaR siRNA group, compared with the hypoxia and negative siRNA groups, the L-NAME group had lower levels of PKG and sGC compared with the ETaR siRNA group. Conclusion: ETaR siRNA is capable of down-regulating the expression of inflammatory and transcription factors among endothelial cells treated with hypoxia. Down-regulation of ET-1 is triggered by altered nucleus transcription factor activity through the sGC/PKG signal pathway, and results in enhanced eNOS activity through the PI3K/Akt signal pathway. We suspect this to be the mechanism of the protective effect of ETaR siRNA.
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Rosanò, Laura, Francesca Spinella, and Anna Bagnato. "The importance of endothelin axis in initiation, progression, and therapy of ovarian cancer." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 299, no. 2 (August 2010): R395—R404. http://dx.doi.org/10.1152/ajpregu.00304.2010.
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The endothelin-1 (ET-1)/ET A receptor (ETAR) axis is involved in the pathobiology of different tumors, including ovarian carcinoma. Acting selectively on ETAR, ET-1 regulates, through multiple signaling pathways, mitogenesis, cell survival, angiogenesis, lymphangiogenesis, invasion, and metastatic dissemination. Moreover, ET-1/ETAR axis appears to be critical in epithelial-to-mesenchymal transition (EMT), providing a mechanism of escape to a new, less adverse niche, in which resistance to apoptosis ensures cell survival in conditions of stress in the primary tumor, and acquisition of “stemness” ensures generation of the critical mass required for tumor progression. Emerging experimental and preclinical data demonstrate that interfering with ETAR pathways provides an opportunity for the development of new mechanism-based antitumor strategies by using ETAR antagonists alone and in combination with cytotoxic drugs or molecular inhibitors. A specific ETAR antagonist in combination with standard chemotherapy is currently evaluated in clinical and translational studies to provide us with new options to treat ovarian cancer and to predict response to therapy. Deeper understanding of molecular mechanism activated by ETAR in ovarian cancer will be of paramount importance in the study of ETAR-targeted therapy that, regulating EMT and other tumor-associated processes, represents an attractive but challenging approach to improve clinical management of ovarian cancer.
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Stanhewicz, Anna E., Sandeep Jandu, Lakshmi Santhanam, and Lacy M. Alexander. "Alterations in endothelin type B receptor contribute to microvascular dysfunction in women who have had preeclampsia." Clinical Science 131, no. 23 (November 23, 2017): 2777–89. http://dx.doi.org/10.1042/cs20171292.
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Microvascular dysfunction originating during a preeclamptic pregnancy persists postpartum and probably contributes to increased CVD risk in these women. One putative mechanism contributing to this dysfunction is increased vasoconstrictor sensitivity to endothelin-1 (ET-1), mediated by alterations in ET-1 receptor type-B (ETBR). We evaluated ET-1 sensitivity, ETAR, and ETBR contributions to ET-1-mediated constriction, and the mechanistic role of ETBR in endothelium-dependent dilation in vivo in the microvasculature of postpartum women who had preeclampsia (PrEC, n=12) and control women who had a healthy pregnancy (HC, n=12). We hypothesized that (1) PrEC would have a greater vasoconstrictor response to ET-1, and (2) reduced ETBR-mediated dilation. We further hypothesized that ETBR-blockade would attenuate endothelium-dependent vasodilation in HC, but not PrEC. Microvascular reactivity was assessed by measurement of cutaneous vascular conductance responses to graded infusion of ET-1 (10−20–10−8 mol/l), ET-1 + 500 nmol/l BQ-123 (ETAR-blockade), and ET-1 + 300 nmol/l BQ-788 (ETBR-blockade), and during graded infusion of acetylcholine (ACh, 10−7–102 mmol/l) and a standardized local heating protocol with and without ETBR-inhibition. PrEC had an increased vasoconstriction response to ET-1 (P=0.02). PrEC demonstrated reduced dilation responses to selective ETBR stimulation with ET-1 (P=0.01). ETBR-inhibition augmented ET-1-mediated constriction in HC (P=0.01) but attenuated ET-1-mediated constriction in PrEC (P=0.003). ETBR-inhibition attenuated endothelium-dependent vasodilation responses to 100mmol/l ACh (P=0.04) and local heat (P=0.003) in HC but increased vasodilation (ACh: P=0.01; local heat: P=0.03) in PrEC. Women who have had preeclampsia demonstrate augmented vasoconstrictor sensitivity to ET-1, mediated by altered ETBR signaling. Furthermore, altered ETBR function contributes to diminished endothelium-dependent dilation in previously preeclamptic women.
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Olave, Nelida, Teodora Nicola, Wei Zhang, Arlene Bulger, Masheika James, Suzanne Oparil, Yiu-Fai Chen, and Namasivayam Ambalavanan. "Transforming growth factor-β regulates endothelin-1 signaling in the newborn mouse lung during hypoxia exposure." American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no. 9 (May 1, 2012): L857—L865. http://dx.doi.org/10.1152/ajplung.00258.2011.
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We have previously shown that inhibition of transforming growth factor-β (TGF-β) signaling attenuates hypoxia-induced inhibition of alveolar development and abnormal pulmonary vascular remodeling in the newborn mice and that endothelin-A receptor (ETAR) antagonists prevent and reverse the vascular remodeling. The current study tested the hypothesis that inhibition of TGF-β signaling attenuates endothelin-1 (ET-1) expression and thereby reduces effects of hypoxia on the newborn lung. C57BL/6 mice were exposed from birth to 2 wk of age to either air or hypoxia (12% O2) while being given either BQ610 (ETAR antagonist), BQ788 (ETBR antagonist), 1D11 (TGF-β neutralizing antibody), or vehicle. Lung function and development and TGF-β and ET-1 synthesis were assessed. Hypoxia inhibited alveolar development, decreased lung compliance, and increased lung resistance. These effects were associated with increased TGF-β synthesis and signaling and increased ET-1 synthesis. BQ610 (but not BQ788) improved lung function, without altering alveolar development or increased TGF-β signaling in hypoxia-exposed animals. Inhibition of TGF-β signaling reduced ET-1 in vivo, which was confirmed in vitro in mouse pulmonary endothelial, fibroblast, and epithelial cells. ETAR blockade improves function but not development of the hypoxic newborn lung. Reduction of ET-1 via inhibition of TGF-β signaling indicates that TGF-β is upstream of ET-1 during hypoxia-induced signaling in the newborn lung.
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Farhat, Hala, and Bruce G. Allen. "Salicylic acid alters endothelin-1 binding in intact adult rat ventricular myocytes." Biochemistry and Cell Biology 82, no. 6 (December 1, 2004): 728–38. http://dx.doi.org/10.1139/o04-125.
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Endothelin receptors ETAR and ETBR form tight receptorligand complexes that complicate our understanding of the physiological, pharmacological, and biochemical properties of these receptors. Although radioligandbinding studies have demonstrated the binding of endothelin-1 (ET-1) to ETAR to be essentially irreversible, ETAR internalize in a ligand-dependent manner, release ET-1, and then recycle to the cell surface. Salicylic acid (SA) reduces ET-1 binding (IC50 = 10 mmol/L) to recombinant ETAR in isolated membranes by promoting dissociation of [125I]ET-1. In the present study, SA (5 mmol SA/L) did not alter [125I]ET-1 binding to intact adult rat ventricular myocytes. The lack of effect was not due to internalization of receptorligand complexes. However, 100 mmol SA/L significantly reduced [125I]ET-1 binding to both intact myocytes and isolated membranes. SA induced the phosphorylation p42/44 extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase and an unidentified 40-kDa protein on the activating threonine-glutamic acid-tyrosine (T-E-Y) motif. ERK phosphorylation was reduced by a MAP kinase kinase (MEK) inhibitor, PD98059. Phosphorylation of p40 was reduced by the p38 MAP kinase inhibitor SB203580, but not PD98059. However, inhibition of ERK or p38 MAP kinases did not alter the ability of 100 mmol SA/L to induce dissociation of [125I]ET-1. These results suggest that, in the ventricular myocyte, salicylic acid alters the kinetics of ET-1 binding. The results also suggest an allosteric binding site may be present that modulates the dissociation of ET-1 receptorligand complexes in response to an as-of-yet unidentified mediator.Key words: cell communication, endothelin, endothelin receptor, inotropic agents, signal transduction, heart, ventricular myocyte.
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Stölting, Miriam, Christiane Geyer, Anne Helfen, Anke Hahnenkamp, Marco V. Usai, Eva Wardelmann, Michael T. Kuhlmann, Moritz Wildgruber, and Carsten Höltke. "Monitoring Endothelin-A Receptor Expression during the Progression of Atherosclerosis." Biomedicines 8, no. 12 (November 26, 2020): 538. http://dx.doi.org/10.3390/biomedicines8120538.
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Cardiovascular disease remains the most frequent cause of death worldwide. Atherosclerosis, an underlying cause of cardiovascular disease, is an inflammatory disorder associated with endothelial dysfunction. The endothelin system plays a crucial role in the pathogenesis of endothelial dysfunction and is involved in the development of atherosclerosis. We aimed to reveal the expression levels of the endothelin-A receptor (ETAR) in the course of atherogenesis to reveal possible time frames for targeted imaging and interventions. We used the ApoE−/− mice model and human specimens and evaluated ETAR expression by quantitative rtPCR (qPCR), histology and fluorescence molecular imaging. We found a significant upregulation of ETAR after 22 weeks of high-fat diet in the aortae of ApoE−/− mice. With regard to translation to human disease, we applied the fluorescent probe to fresh explants of human carotid and femoral artery specimens. The findings were correlated with qPCR and histology. While ETAR is upregulated during the progression of early atherosclerosis in the ApoE−/− mouse model, we found that ETAR expression is substantially reduced in advanced human atherosclerotic plaques. Moreover, those expression changes were clearly depicted by fluorescence imaging using our in-house designed ETAR-Cy 5.5 probe confirming its specificity and potential use in future studies.
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Mücke, Marcus M., Dominik Bettenworth, Christiane Geyer, Katrin Schwegmann, Christopher Poremba, Michael Schäfers, Dirk Domagk, Carsten Höltke, and Philipp Lenz. "Targeting Mucosal Endothelin-A-Receptor Expression by Fluorescence Endoscopy is Feasible to Detect and Characterize Colitis-Associated Cancer in Mice." Inflammatory Bowel Diseases 24, no. 1 (December 19, 2017): 111–22. http://dx.doi.org/10.1093/ibd/izx032.
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Abstract Background To facilitate onsite decision-making during endoscopy, both accurate detection and in vivo characterization of preneoplasia are prerequisites. However, no endoscopy technique is available that meets both demands satisfactorily. We evaluated endothelin-receptor A (ETAR)-guided fluorescence endoscopy (FE) in vivo and fluorescence reflectance imaging (FRI) ex vivo for detection and characterization of early dysplastic colitis-associated colonic lesions. Methods Colorectal cancerogenesis was investigated in the inflammatory driven AOM-DSS model and spontaneous adenoma development in ApcMin mice. A Cy5.5-labeled nonpeptidic ETAR-specific imaging probe was injected intravenously to assess tumor development in vivo by white light endoscopy (WLE) and FE. Ex vivo tumors were evaluated by FRI, histological examination, and western blot analysis. In addition, tissue samples from patients with colitis-associated malignant and nonmalignant mucosal alterations were analyzed. Specificity experiments were performed using an unspecific Cy3.5-glycine tracer. Results Overall, 62 adenomas were observed. FE was able to detect and quantify ETAR expression targeting the ETAR-specific photoprobe. A significantly higher fluorescent contrast was detected in colonic adenomas compared to adjacent nonmalignant mucosa by FE (64.3 ± 7.9 vs. 56.6. ± 7.0; P < 0.001). These results were confirmed by FRI examination, immunochemistry, and western blot analysis. Additionally, ETAR expression in samples from human patients with colitis-associated cancer was highly elevated compared to nonmalignant alterations. Specificity experiments indicated a high binding-specificity of the applied ETAR photoprobe (1.4 ± 0.3 vs. 2.5 ± 0.7; P < 0.001). Conclusions We introduced ETAR guided FE in mice for successful in vivo detection and characterization of colorectal neoplasia on a molecular level.
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Cianfrocca, Roberta, Laura Rosanò, Francesca Spinella, Valeriana Di Castro, Pier Giorgio Natali, and Anna Bagnato. "β-arrestin-1 mediates the endothelin-1-induced activation of Akt and integrin-linked kinaseThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research." Canadian Journal of Physiology and Pharmacology 88, no. 8 (August 2010): 796–801. http://dx.doi.org/10.1139/y10-052.
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The contribution of the endothelin-1 (ET-1)/ET A receptor (ETAR) axis in tumor growth and progression is investigated in many tumor types, including ovarian carcinoma. In ovarian cancer cells, ET-1 acts as an autocrine growth factor selectively through the ETAR triggering the concomitant activation of multiple pathways. In these cells, the involvement of β-arrestin-1 as signal transducer in ET-1-dependent signalling pathways has been recently highlighted. Because several G protein-coupled receptors have been shown to activate signalling pathways in a β-arrestin-dependent manner, in this study we explored whether β-arrestin-1 is involved in a distinct signalling mechanism linking the ETAR to phosphoinositide 3-kinase (PI3K)/integrin-linked kinase (ILK)/Akt in HEY ovarian cancer cells. The inhibitory effects of ZD4054 (zibotentan), a specific ETAR antagonist, in ET-1-dependent phosphorylation of ILK, Akt, and glycogen synthase kinase (GSK-3β) demonstrated the involvement of the ETAR in these effects. By using a kinase assay, we demonstrate that β-arrestin-1 silencing inhibits the ET-1-induced ILK activity in a time-dependent manner and downstream Akt and GSK-3β phosphorylation. These results reveal that β-arrestin-1 is implicated as an ETAR-transducer in the activation of ILK and Akt and in the inactivation of GSK-3β in response to ET-1 and further support the role of β-arrestin-1 as a multifunctional adaptor facilitating interprotein interactions critically involved in ETAR-mediated signalling that regulate invasive and metastatic behaviour of ovarian cancer.
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Lin, ChengCheng, XiaoYun Wu, YuLei Zhou, Bei Shao, XiaoTing Niu, WanLi Zhang, and YuanShao Lin. "Maternal high-fat diet programs cerebrovascular remodeling in adult rat offspring." Journal of Cerebral Blood Flow & Metabolism 38, no. 11 (September 15, 2017): 1954–67. http://dx.doi.org/10.1177/0271678x17731956.
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Maternal environmental factors such as diet have consequences on later health of the offspring. We found that maternal high-fat diet (HFD) exposure renders adult offspring brain more susceptible to ischemic injury. The present study was further to investigate whether HFD consumption during rat pregnancy and lactation influences the cerebral vasculature in adult male offspring. Besides the endothelial damage observed in the transmission electron microscopy, the MCAs of offspring from fat-fed dams fed with control diet (HFD/C) also displayed increased wall thickness and media/lumen ratio, suggesting that cerebrovascular hypertrophy or hyperplasia occurs. Moreover, smaller lumen diameter and elevated myogenic tone of the MCAs over a range of intralumenal pressures indicate inward cerebrovascular remodeling in HFD/C rats, with a concomitant increase in vessel stiffness. More importantly, both wire and pressure myography demonstrated that maternal HFD intake also enhanced the MCAs contractility to ET-1, accompanied by increases in ET types A receptor (ETAR) but not B (ETBR) density in the arteries. Furthermore, ETAR antagonism but not ETBR antagonism restored maternal HFD-induced cerebrovascular dysfunction in adult offspring. Taken together, maternal diet can substantially influence adult offspring cerebrovascular health, through remodeling of both structure and function, at least partially in an ET-1 manner.
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Garcia-Marcos, Mikel, and Annalisa M. VanHook. "Science Signaling Podcast for 12 April 2016: G proteins in auriculo-condylar syndrome." Science Signaling 9, no. 423 (April 12, 2016): pc9. http://dx.doi.org/10.1126/scisignal.aaf7740.
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AbstractThis Podcast features an interview with Mikel Garcia-Marcos, author of a Research Article that appears in the 12 April 2016 issue of Science Signaling, about how mutations in a G protein cause auriculo-condylar syndrome (ACS). ACS is caused by mutations that affect signaling through the endothelin type A receptor (ETAR) and is characterized by craniofacial abnormalities resulting from defects in neural crest development. ETAR is a G protein–coupled receptor (GPCR) that signals primarily through heterotrimeric G proteins containing Gαq/11, but mutations in Gαi3 are also associated with ACS. Marivin et al. found that ETAR coupled to ACS-associated mutant forms of Gαi3 instead of coupling to Gαq/11. These mutant forms of Gαi3 lacked enzymatic activity and thus blocked ETAR signaling.Listen to Podcast
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Intagliata, Sebastiano, Mohamed A. Helal, Luisa Materia, Valeria Pittalà, Loredana Salerno, Agostino Marrazzo, Alfredo Cagnotto, Mario Salmona, Maria N. Modica, and Giuseppe Romeo. "Synthesis and Molecular Modelling Studies of New 1,3-Diaryl-5-Oxo-Proline Derivatives as Endothelin Receptor Ligands." Molecules 25, no. 8 (April 17, 2020): 1851. http://dx.doi.org/10.3390/molecules25081851.
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The synthesis of seventeen new 1,3-diaryl-5-oxo-proline derivatives as endothelin receptor (ETR) ligands is described. The structural configuration of the new molecules was determined by analyzing selected signals in proton NMR spectra. In vitro binding assays of the human ETA and ETB receptors allowed us to identify compound 31h as a selective ETAR ligand. The molecular docking of the selected compounds and the ETA antagonist atrasentan in the ETAR homology model provided insight into the structural elements required for the affinity and the selectivity of the ETAR subtype.
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Civieri, Giovanni, Laura Iop, and Francesco Tona. "Antibodies against Angiotensin II Type 1 and Endothelin 1 Type A Receptors in Cardiovascular Pathologies." International Journal of Molecular Sciences 23, no. 2 (January 15, 2022): 927. http://dx.doi.org/10.3390/ijms23020927.
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Angiotensin II receptor type 1 (AT1R) and endothelin-1 receptor type A (ETAR) are G-protein-coupled receptors (GPCRs) expressed on the surface of a great variety of cells: immune cells, vascular smooth cells, endothelial cells, and fibroblasts express ETAR and AT1R, which are activated by endothelin 1 (ET1) and angiotensin II (AngII), respectively. Certain autoantibodies are specific for these receptors and can regulate their function, thus being known as functional autoantibodies. The function of these antibodies is similar to that of natural ligands, and it involves not only vasoconstriction, but also the secretion of proinflammatory cytokines (such as interleukin-6 (IL6), IL8 and TNF-α), collagen production by fibroblasts, and reactive oxygen species (ROS) release by fibroblasts and neutrophils. The role of autoantibodies against AT1R and ETAR (AT1R-AAs and ETAR-AAs, respectively) is well described in the pathogenesis of many medical conditions (e.g., systemic sclerosis (SSc) and SSc-associated pulmonary hypertension, cystic fibrosis, and allograft dysfunction), but their implications in cardiovascular diseases are still unclear. This review summarizes the current evidence regarding the effects of AT1R-AAs and ETAR-AAs in cardiovascular pathologies, highlighting their roles in heart transplantation and mechanical circulatory support, preeclampsia, and acute coronary syndromes.
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Moon, Henry H., Katrina L. Clines, Mark A. Cooks, Charlotte A. Cialek, Marian A. Esvelt, and Gregory A. Clines. "Castration Determines the Efficacy of ETAR Blockade in a Mouse Model of Prostate Cancer Bone Metastasis." Endocrinology 160, no. 8 (June 7, 2019): 1786–96. http://dx.doi.org/10.1210/en.2019-00261.
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Abstract Bone metastasis is a painful complication of advanced prostate cancer. Endothelin-1 is a tumor-secreted factor that plays a central role in osteoblast activation and the osteosclerotic response of prostate cancer metastatic to bone. Antagonists that block the activation of the endothelin A receptor (ETAR), located on osteoblasts, reduce osteoblastic bone lesions in animal models of bone metastasis. However, ETAR antagonists demonstrated limited efficacy in clinical trials of men with advanced prostate cancer who also received standard androgen deprivation therapy (ADT). Previous data from our group suggested that, in a mouse model, ETAR antagonists might only be efficacious when androgen signaling in the osteoblast is lowered beyond the ability of standard ADT. This notion was tested in a mouse model of prostate cancer bone metastasis. Castrated and sham-operated male athymic nude mice underwent intracardiac inoculation of the ARCaPM castration-resistant prostate cancer cell line. The mice were then treated with either the ETAR antagonist zibotentan or a vehicle control to generate four experimental groups: vehicle+sham (Veh+Sham), vehicle+castrate (Veh+Castr), zibotentan+sham (Zibo+Sham), and zibotentan+castrate (Zibo+Castr). The mice were monitored radiographically for the development of skeletal lesions. The Zibo+Castr group had significantly longer survival and a single incidental lesion. Mice in the Zibo+Sham group had the shortest survival and the largest number of skeletal lesions. Survival and skeletal lesions of the Veh+Sham and Veh+Castr groups were intermediate compared with the zibotentan-treated groups. We report a complex interaction between ETAR and androgen signaling, whereby ETAR blockade was most efficacious when combined with complete androgen deprivation.
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Albert, Christian, Marie Schultzendorff, Delia Şalaru, Zuhir Halloul, Duska Dragun, Harald Heidecke, and Peter R. Mertens. "In arterial occlusive disease autoantibodies against ETAR and AT1R correlate with each other but are not associated with classical cardiovascular risk factors." Vasa 43, no. 2 (March 1, 2014): 113–23. http://dx.doi.org/10.1024/0301-1526/a000337.
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Background: Autoantibodies (Abs) against angiotensin-II type 1 (AT1R) and endothelin-1 type A receptors (ETAR) are investigated in the present study as B-cell originated humoral factors that may activate the respective receptors on endothelial cells. The prevalence of the Abs was determined in patients with peripheral arterial occlusive disease (PAD). Patients and methods: In a prospective observational study 200 patients undergoing angiography and proven advanced PAD were enrolled. Serum samples, clinical data and laboratory values for classical cardiovascular risk factors were collected. Autoantibody titers for AT1R and ETAR were determined by solid-phase ELISA and correlative analyses with laboratory parameters and clinical data for common cardiovascular risk factors were performed. Results: Anti-ETAR antibody titers were detected in 57 % of the patients, elevated anti-AT1R titers in 61.5 %. About 50 % were positive for both Abs. A strong intercorrelation between ETAR and AT1R titers was present (r2 0.79). In patients with positive titers for both Abs females presented significantly higher titers for ETAR (p = 0.045) and AT1R (p = 0.02). Autoantibody titers directed against surface receptors ETA and AT1 are highly correlated in PAD. Titers were independent from classical risk factors in any patient subgroup. Conclusions: This study opens a new perspective on the involvement of the immune system, hereby represented by functional autoantibodies, in the atherosclerotic pathophysiology, leaving behind the common background of classical risk factors.
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Xiong, Xinyu, Nour Nazo, Ritika Revoori, Sudarshan Rajagopal, and Matthew A. Sparks. "G protein- and β-arrestin Signaling Profiles of Endothelin Derivatives at the Type A Endothelin Receptor." Kidney360 2, no. 7 (May 17, 2021): 1124–31. http://dx.doi.org/10.34067/kid.0005462020.
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AbstractBackgroundEndothelin-1 (ET-1) is a potent vasoconstrictor in the cardiovascular system, an effect mediated through the type A endothelin receptor (ETAR), a G protein-coupled receptor (GPCR). Antagonists of the ETAR have shown promising results in randomized clinical trials. However, side effects limit widespread use. Biased agonists have been developed to mitigate the untoward effects of a number of GPCR antagonists. These agents block deleterious G-coupled pathways while stimulating protective β-arrestin pathways. The goal of this study was to test whether there was any significant ligand bias between endothelin derivatives, and whether this could have any physiologic effects in the cardiovascular system.MethodsA panel of endothelin derivatives were tested in assays of G protein signaling and β-arrestin 2 recruitment at the ETAR. We then tested the effects of ET-1 on the vasopressor response in wild-type and β-arrestin 1 and 2 KO mice.ResultsWe found the endothelins activated a wide range of G proteins at the ETAR, but none of the endothelin derivatives demonstrated significant biased agonism. Endothelin derivatives did display structure-activity relationships with regards to their degrees of agonism. β-arrestin 1 and 2 knockout mice did not display any differences to wild-type mice in the acute pressor response to ET-1, and β-arrestin 2 knockout mice did not display any blood pressure differences to wild-type mice in the chronic responses to ET-1.ConclusionsOur findings are consistent with vasoconstriction being mediated by G proteins with a lack of significant desensitization by β-arrestins at the ETAR. These findings suggest that G protein– and β-arrestin–biased ETAR agonists could have distinct physiologic effects from balanced agonists, although the endothelin peptide scaffold does not appear suitable for designing such ligands.
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Funke, Carsten, Martin Farr, Bianca Werner, Sven Dittmann, Klaus Überla, Cornelia Piper, Karsten Niehaus, and Dieter Horstkotte. "Antiviral effect of Bosentan and Valsartan during coxsackievirus B3 infection of human endothelial cells." Journal of General Virology 91, no. 8 (August 1, 2010): 1959–70. http://dx.doi.org/10.1099/vir.0.020065-0.
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In viral myocarditis, adeno- and enteroviruses have most commonly been implicated as causes of infection. Both viruses require the human coxsackie-adenovirus receptor (CAR) to infect the myocardium. Due to its crucial role for viral entry, CAR-downregulation may lead to novel approaches for treatment for viral myocarditis. In this study, we report on pharmaceutical drug influences on CAR levels in human umbilical vein endothelial cells (HUVEC) and cervical carcinoma cells (HeLa) detected by immunoblotting, quantitative real time-PCR and cellular susceptibility to the cardiotropic coxsackie-B3 virus strain Nancy (CVB3). Our results indicate, for the first time, a dose-dependent CAR mRNA and protein downregulation upon Valsartan and Bosentan treatment. Most interestingly, drug-induced CAR diminution significantly reduced the viral load in CVB3-infected HUVEC. In order to assess the regulatory effects of both drugs in detail, we knocked down their protein targets, the G-protein coupled receptors angiotensin-II type-1 receptor (AT1R) and endothelin-1 type-A and -B receptors (ETAR/ETBR) in HUVEC. Receptor-specific gene silencing indicates that CAR gene expression is regulated by agonistic and antagonistic binding to ETBR, but not ETAR. In addition, neither stimulation nor inhibition of AT1R seemed to be involved in CAR gene regulatory processes. Our study indicates that Valsartan and Bosentan protected human endothelial cells from CVB3-infection. Therefore, besides their well-known anti-hypertensive effects these drugs may also protect the myocardium and other tissues from coxsackie- and adenoviral infection.
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Büther, Katrin, Matthijs G. Compeer, Jo G. R. De Mey, Otmar Schober, Michael Schäfers, Christoph Bremer, Burkhard Riemann, and Carsten Höltke. "Assessment of Endothelin-A Receptor Expression in Subcutaneous and Orthotopic Thyroid Carcinoma Xenografts in Vivo Employing Optical Imaging Methods." Endocrinology 153, no. 6 (April 17, 2012): 2907–18. http://dx.doi.org/10.1210/en.2011-2017.
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Endothelin (ET) receptor dysregulation has been described in a number of pathophysiological processes, including cardiovascular disorders, renal failure, and cancer. The aim of this study was to evaluate the expression of the ET-A receptor (ETAR) in murine models of thyroid carcinoma using optical imaging methods. A recently developed near-infrared fluorescent tracer was first assessed in isolated artery preparations for its functional performance in comparison with known ETAR antagonists BQ123 and PD156707. Before evaluation of the tracer in vivo, different thyroid carcinoma cell lines were characterized with respect to their ET receptor expression by RT-PCR and autoradiography. In vivo, sc and orthotopic papillary thyroid tumor xenografts were clearly visualized by fluorescence reflectance imaging and fluorescence-mediated tomography up to 48 h after injection of the tracer. Binding specificity of the probe was demonstrated by predosing with PD156707 as a competing inhibitor. In conclusion, optical imaging with a fluorescent ETAR tracer allows the noninvasive imaging of tumor-associated ETAR expression in vivo. In the future, this technique may help surgeons to evaluate lesion dimensions in intraoperative settings (e.g. thyroidectomy).
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Yanes, Licy L., Damian G. Romero, Valeria E. Cucchiarelli, Lourdes A. Fortepiani, Celso E. Gomez-Sanchez, Francisco Santacruz, and Jane F. Reckelhoff. "Role of endothelin in mediating postmenopausal hypertension in a rat model." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 288, no. 1 (January 2005): R229—R233. http://dx.doi.org/10.1152/ajpregu.00697.2003.
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Cardiovascular disease is the leading cause of death in women after menopause. Hypertension, a major cardiovascular risk factor, becomes more prevalent after menopause. The mechanisms responsible for the increase in blood pressure (BP) in postmenopausal women are unknown. We have recently characterized the aged, postestrous-cycling (PMR) spontaneously hypertensive rats (SHR) as a model of postmenopausal hypertension. The purpose of the present study was to determine whether endothelin plays a role in the increased BP in PMR. Premenopausal female SHR, aged 4–5 mo (YF), and PMR, aged 16 mo, were studied. Expression of preproendothelin-1 mRNA was not different in either renal cortex or medulla between PMR and YF ( n = 7–8/group). In contrast, ET-1 peptide expression was significantly higher in renal cortex of PMR than in renal cortex of YF, but there was no difference in medullary ET-1. Expression of endothelin ETA receptor (ETAR) mRNA was lower in renal cortex and medulla of PMR than of YF. Additional groups of rats ( n = 6–7/group) were treated for 3 wk with the ETAR antagonist ABT-627 (5 mg·kg−1·day−1). BP was significantly higher in PMR than in YF. ETAR antagonist reduced BP in PMR by 20% to the level found in control YF. ETAR antagonist had no effect on BP in YF. These data support the hypothesis that the increase in BP in PMR is mediated in part by endothelin and the ETAR.
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Kohl, Tobias, Melanie von Brandenstein, Andreas Stog, Monika Schlosser, Timur H. Kuru, David Pfister, Jochen Fries, and Axel Heidenreich. "Vimentin 3 and endothelin in prostate cancer." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 349. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.349.
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349 Background: An upregulation of vimentin 3, a truncated version of the full length vimentin, with an unknown function, was previously described by our group, in a direct dependency of increased ET-1 levels. We analyzed now vimentin 3 in further genitourinary cancers. Here, we describe our findings how vimentin 3 is part of the signaling pathways from Endothelin-1 (ET-1) and the Endothelin-A-Receptor (ETAR) and how it correlates with aggressive tumor behavior in a PCa cell culture and in human tissue and serum samples from PCa patients. Methods: DU145 cells were cultured. We stimulated with ET-1 with and without artificial downregulation of the ETAR, the ETBR or both receptors. A scratch assay was performed to demonstrate the influence of ET-1. Proteins were then extracted and WB for vimentin full length and vimentin 3 was performed. Additionally we analyzed ET-1 and vimentin 3 in serum from prostate cancer patients using ELISA and we did IF and IHC staining for vimentin 3 in human prostate cancer tissue. Results: Treatment with ET-1 and downregulation of the ETBR lead to a significant increased migration of DU145 cells after 3 and 6 h. The corresponding WB showed increased vimentin 3. ELISA showed increased levels of ET-1 in samples of prostate cancer patients compared to patients with no cancer history. ELISA could also demonstrate elevated levels of vimentin 3 in serum of patients with local disease and significantly elevated values in metastatic prostate cancer patients compared to patients with no cancer history. Conclusions: The data presented shows that ET-1 stimulation leads to overexpression of vimentin 3 in prostate cancer cell cultures and a concomitant aggressive biological behavior. Here we previously described the direct interaction of Vimentin 3 in prostate cancer and the activation mechanism via ET-1 and the ETAR. IHC, IF show an upregulation of the truncated variant Vimentin3 in tissue samples. In an Vimentin 3 ELISA we could show that this truncated variant is increased and therefore represents a potential biomarker. Highest values of vimentin 3 were measured using ELISA in serum of patients with recurrent and metastatic disease also suggesting that vimentin 3 correlates with aggressive tumor behavior.
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Avouac, Jérôme, Gabriela Riemekasten, Christophe Meune, Barbara Ruiz, André Kahan, and Yannick Allanore. "Autoantibodies against Endothelin 1 Type A Receptor Are Strong Predictors of Digital Ulcers in Systemic Sclerosis." Journal of Rheumatology 42, no. 10 (August 1, 2015): 1801–7. http://dx.doi.org/10.3899/jrheum.150061.
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Objective.To determine the predictive value of functional autoantibodies against vascular receptors for the development of ischemic digital ulcers (DU) in patients with systemic sclerosis (SSc).Methods.Angiotensin II Type 1 receptor (AT1R) and endothelin 1 Type A receptor (ETAR) autoantibodies were measured at baseline in a prospective cohort of 90 patients with SSc together with 5 validated angiogenic markers. The primary outcome was the occurrence of at least 1 new ischemic DU during the 5-year followup.Results.Twenty-four patients developed at least 1 new DU during the followup period. Univariate Cox analysis revealed that concentrations above the median value of anti-AT1R and anti-ETAR antibodies were predictive of the occurrence of ischemic DU (HR 2.85, 95% CI 1.19–6.84 and HR 3.39, 95% CI 1.35–8.50, respectively). A first multivariate Cox analysis including functional autoantibodies and clinical predictors of new DU confirmed anti-ETAR autoantibodies as independent predictors of the occurrence of new ischemic DU (HR 3.15, 95% CI 1.22–8.13) together with a history of DU at baseline. In a second model implemented with angiogenic markers, anti-ETAR autoantibodies remained an independent predictor of the occurrence of new ischemic DU (HR 9.59, 95% CI 1.75–52.64) together with the presence at baseline of active DU or history of DU.Conclusion.Anti-ETAR autoantibodies can be used together with the presence of current or past DU to identify patients with SSc who are at risk for the development of subsequent DU. These autoantibodies may allow for earlier management and therapeutic intervention.
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Donkov, Lazar. "Parc-musée ethnographique Etar, Gabrovo." Museum International (Edition Francaise) 28, no. 1 (April 24, 2009): 9–14. http://dx.doi.org/10.1111/j.1755-5825.1976.tb01468.x.
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Siao, An-Ci, Yen-Yue Lin, Li-Jane Shih, Yi-Wei Tsuei, Chih-Pin Chuu, Yow-Chii Kuo, and Yung-Hsi Kao. "Endothelin-1 stimulates preadipocyte growth via the PKC, STAT3, AMPK, c-JUN, ERK, sphingosine kinase, and sphingomyelinase pathways." American Journal of Physiology-Cell Physiology 319, no. 5 (November 1, 2020): C839—C857. http://dx.doi.org/10.1152/ajpcell.00491.2019.
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Endothelin (ET)-1 regulates adipogenesis and the endocrine activity of fat cells. However, relatively little is known about the ET-1 signaling pathway in preadipocyte growth. We used 3T3-L1 preadipocytes to investigate the signaling pathways involved in ET-1 modulation of preadipocyte proliferation. As indicated by an increased number of cells and greater incorporation of bromodeoxyuridine (BrdU), the stimulation of preadipocyte growth by ET-1 depends on concentration and timing. The concentration of ET-1 that increased preadipocyte number by 51–67% was ~100 nM for ~24–48 h of treatment. ET-1 signaling time dependently stimulated phosphorylation of ERK, c-JUN, STAT3, AMPK, and PKCα/βII proteins but not AKT, JNK, or p38 MAPK. Treatment with an ETAR antagonist, such as BQ610, but not ETBR antagonist BQ788, blocked the ET-1-induced increase in cell proliferation and phosphorylated levels of ERK, c-JUN, STAT3, AMPK, and PKCα/βII proteins. In addition, pretreatment with specific inhibitors of ERK1/2 (U0126), JNK (SP600125), JAK2/STAT3 (AG490), AMPK (compound C), or PKC (Ro318220) prevented the ET-1-induced increase in cell proliferation and reduced the ET-1-stimulated phosphorylation of ERK1/2, c-JUN, STAT3, AMPK, and PKCα/β. Moreover, the SphK antagonist suppressed ET-1-induced cell proliferation and ERK, c-JUN, STAT3, AMPK, and PKC phosphorylation, and the SMase2 antagonist suppressed ET-1-induced cell proliferation. However, neither the p38 MAPK antagonist nor the CerS inhibitor altered the effect of ET-1. The results indicate that ETAR, JAK2/STAT3, ERK1/2, JNK/c-JUN, AMPK, PKC, SphK, and SMase2, but not ETBR, p38 MAPK, or CerS, are necessary for the ET-1 stimulation of preadipocyte proliferation.
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Rosanò, Laura, Roberta Cianfrocca, Francesca Spinella, Valeriana Di Castro, Pier Giorgio Natali, and Anna Bagnato. "Combination therapy of zibotentan with cisplatinum and paclitaxel is an effective regimen for epithelial ovarian cancerThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research." Canadian Journal of Physiology and Pharmacology 88, no. 6 (June 2010): 676–81. http://dx.doi.org/10.1139/y10-053.
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In human ovarian carcinoma, the endothelin-1 (ET-1) / endothelin A receptor (ETAR) axis is overexpressed, correlating with tumor grade. Moreover, ETAR activation by ET-1 affects cell proliferation, survival, angiogenesis, and invasion. ETAR blockade with zibotentan (ZD4054), a specific ETAR antagonist, significantly inhibits ovarian cancer growth in vitro and in vivo, underscoring the relevance of this pathway as a target for cancer therapy. Since clinical trial results have defined the combination of platinum and taxane as the standard of care in the management of ovarian cancer, here we explored the therapeutic efficacy of the integration of zibotentan with cytotoxic drugs having different modes of action. We found that the combination of zibotentan with cisplatinum as well as zibotentan with paclitaxel was more effective at inhibiting ovarian cancer HEY cell proliferation induced by endogenous ET-1 than were the single agents alone. However, a significantly enhanced efficacy was observed when we combined zibotentan, cisplatinum, and paclitaxel. Accordingly, in HEY xenografts the coadministration of zibotentan with cisplatinum enhanced the efficacy of the cytotoxic drug alone in controlling tumor growth, associated with reduction in proliferation index and microvessel density. Remarkably, the combination of zibotentan with both cisplatinum and paclitaxel was very effective in inhibiting tumor growth, neovascularization, and cell proliferation, representing a preclinical endpoint to guide combination therapy in clinical trials.
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Mikhail, Marianne, Pierre H. Vachon, Pedro D’Orléans-Juste, Danielle Jacques, and Ghassan Bkaily. "Role of endothelin-1 and its receptors, ETAand ETB, in the survival of human vascular endothelial cells." Canadian Journal of Physiology and Pharmacology 95, no. 10 (October 2017): 1298–305. http://dx.doi.org/10.1139/cjpp-2017-0412.
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Our previous work showed the presence of endothelin-1 (ET-1) receptors, ETAand ETB, in human vascular endothelial cells (hVECs). In this study, we wanted to verify whether ET-1 plays a role in the survival of hVECs via the activation of its receptors ETAand (or) ETB(ETAR and ETBR, respectively). Our results showed that treatment of hVECs with ET-1 prevented apoptosis induced by genistein, an effect that was mimicked by treatment with ETBR-specific agonist IRL1620. Furthermore, blockade of ETBR with the selective ETBR antagonist A-192621 prevented the anti-apoptotic effect of ET-1 in hVECs. However, activation of ETAreceptor alone did not seem to contribute to the anti-apoptotic effect of ET-1. In addition, the anti-apoptotic effect of ETBR was found to be associated with caspase 3 inhibition and does not depend on the density of this type of receptor. In conclusion, our results showed that ET-1 possesses an anti-apoptotic effect in hVECs and that this effect is mediated, to a great extent, via the activation of ETBR. This study revealed a new role for ETBR in the survival of hVECs.
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Riemekasten, Gabriela, Aurélie Philippe, Melanie Näther, Torsten Slowinski, Dominik N. Müller, Harald Heidecke, Marco Matucci-Cerinic, et al. "Involvement of functional autoantibodies against vascular receptors in systemic sclerosis." Annals of the Rheumatic Diseases 70, no. 3 (November 15, 2010): 530–36. http://dx.doi.org/10.1136/ard.2010.135772.
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BackgroundSystemic sclerosis (SSc) features autoimmunity, vasculopathy and tissue fibrosis. The renin-angiotensin and endothelin systems have been implicated in vasculopathy and fibrosis. A role for autoantibody-mediated receptor stimulation is hypothesised, linking three major pathophysiological features consistent with SSc.MethodsSerum samples from 478 patients with SSc (298 in the study cohort and 180 from two further independent cohorts), 372 healthy subjects and 311 control-disease subjects were tested for antibodies against angiotensin II type 1 receptor (AT1R) and endothelin-1 type A receptor (ETAR) by solid phase assay. Binding specificities were tested by immunoprecipitation. The biological effects of autoantibodies in microvascular endothelial cells in vitro were also determined, as well as the quantitative differences in autoantibody levels on specific organ involvements and their predictive value for SSc-related mortality.ResultsAnti-AT1R and anti-ETAR autoantibodies were detected in most patients with SSc. Autoantibodies specifically bound to respective receptors on endothelial cells. Higher levels of both autoantibodies were associated with more severe disease manifestations and predicted SSc-related mortality. Both autoantibodies exert biological effects as they induced extracellular signal-regulated kinase 1/2 phosphorylation and increased transforming growth factor β gene expression in endothelial cells which could be blocked with specific receptor antagonists.ConclusionsFunctional autoimmunity directed at AT1R and ETAR is common in patients with SSc. AT1R and ETAR autoantibodies could contribute to disease pathogenesis and may serve as biomarkers for risk assessment of disease progression.
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Lozano, E., M. Segarra, M. Corbera-Bellalta, A. García-Martínez, G. Espígol-Frigolé, A. Plà-Campo, J. Hernández-Rodríguez, and M. C. Cid. "Increased expression of the endothelin system in arterial lesions from patients with giant-cell arteritis: association between elevated plasma endothelin levels and the development of ischaemic events." Annals of the Rheumatic Diseases 69, no. 2 (March 15, 2009): 434–42. http://dx.doi.org/10.1136/ard.2008.105692.
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Objective:Approximately 15–20% of patients with giant-cell arteritis (GCA) develop ischaemic complications often preceded by transient ischaemia. The expression of the endothelin (ET) system in GCA lesions was investigated to assess its relationship with the development of ischaemic complications.Methods:Plasma ET-1 was quantified by immunoassay in 61 patients with biopsy-confirmed GCA and 16 healthy donors. ET-1, endothelin-converting enzyme (ECE-1) and endothelin receptor (ETAR and ETBR) messenger RNA were measured by real-time quantitative reverse transcriptase–PCR in temporal arteries from 35 of these patients and 19 control arteries. Proteins were measured by immunoassay and Western blot.Results:ET-1 concentration was increased at the protein level in temporal artery samples from GCA patients compared with controls (0.98 (SEM 0.32) vs 0.28 (SEM 0.098) fmol/mg, p = 0.028). ECE-1, ETAR and ETBR/actin ratios (Western blot) were also significantly higher in GCA patients. Intriguingly, mRNA expression of ET-1, ECE-1 and both receptors was significantly reduced in GCA lesions compared with control arteries. When investigating mechanisms underlying these results, platelet-derived growth factor and IL-1β, present in GCA lesions, were found to downregulate ET-1 mRNA in cultured human temporal artery-derived smooth muscle cells. Glucocorticoid treatment for 8 days did not result in significantly decreased endothelin tissue concentration (0.87 (SEM 0.2) vs 0.52 (SEM 0.08); p = 0.6). Plasma endothelin concentrations were higher in patients with ischaemic complications (1.049 (SEM 0.48) vs 1.205 (SEM 0.63) pg/ml, p = 0.032).Conclusions:The endothelin system is increased at the protein level in GCA lesions creating a microenvironment prone to the development of ischaemic complications. Recovery induced by glucocorticoids is delayed, indicating persistent exposure to endothelin during initial treatment.
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Marivin, Arthur, Anthony Leyme, Kshitij Parag-Sharma, Vincent DiGiacomo, Anthony Y. Cheung, Lien T. Nguyen, Isabel Dominguez, and Mikel Garcia-Marcos. "Dominant-negative Gα subunits are a mechanism of dysregulated heterotrimeric G protein signaling in human disease." Science Signaling 9, no. 423 (April 12, 2016): ra37. http://dx.doi.org/10.1126/scisignal.aad2429.
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Auriculo-condylar syndrome (ACS), a rare condition that impairs craniofacial development, is caused by mutations in a G protein–coupled receptor (GPCR) signaling pathway. In mice, disruption of signaling by the endothelin type A receptor (ETAR), which is mediated by the G protein (heterotrimeric guanine nucleotide–binding protein) subunit Gαq/11 and subsequently phospholipase C (PLC), impairs neural crest cell differentiation that is required for normal craniofacial development. Some ACS patients have mutations in GNAI3, which encodes Gαi3, but it is unknown whether this G protein has a role within the ETAR pathway. We used a Xenopus model of vertebrate development, in vitro biochemistry, and biosensors of G protein activity in mammalian cells to systematically characterize the phenotype and function of all known ACS-associated Gαi3 mutants. We found that ACS-associated mutations in GNAI3 produce dominant-negative Gαi3 mutant proteins that couple to ETAR but cannot bind and hydrolyze guanosine triphosphate, resulting in the prevention of endothelin-mediated activation of Gαq/11 and PLC. Thus, ACS is caused by functionally dominant-negative mutations in a heterotrimeric G protein subunit.
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ROSANÒ, Laura, Debora SALANI, Valeriana DI CASTRO, Francesca SPINELLA, Pier Giorgio NATALI, and Anna BAGNATO. "Endothelin-1 promotes proteolytic activity of ovarian carcinoma." Clinical Science 103, s2002 (September 1, 2002): 306S—309S. http://dx.doi.org/10.1042/cs103s306s.
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Endothelin-1 (ET-1) is a potent mitogenic and angiogenic factor for ovarian carcinoma cell lines, which acts selectively through the ETA receptor (ETAR). A previous study demonstrated that ET-1 is present at high concentrations in ovarian cancer ascites, indicating a direct role in the progression and metastasis of ovarian carcinoma. In this study, we investigated whether ET-1 could induce production and activation of tumour-associated proteinases in ovarian carcinoma cells. As demonstrated by ELISA, we found that the secretion of matrix metalloproteinase (MMP)-2 and MMP-9, urokinase-type plasminogen activator and plasminogen activator inhibitor type-1 and -2 was upregulated by ET-1 in a dose-dependent manner in the HEY cell line. In addition, the MMPs in ET-1-treated cells are consistently active, as shown by MMP gelatinase activity assay. Finally, we demonstrated that BQ-123, an antagonist of ETAR, inhibited the ET-1-induced tumour protease secretion and activity, suggesting that ET-1/ETAR may play an important role in the progression and metastasis of ovarian carcinoma, activating multiple proteinase cascades.
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AKIMOTO, Masumi, Hiroshi HASHIMOTO, Atsushi MAEDA, Mutsuo SHIGEMOTO, and Katsuko YAMASHITA. "Roles of angiogenic factors and endothelin-1 in gastric ulcer healing." Clinical Science 103, s2002 (September 1, 2002): 450S—454S. http://dx.doi.org/10.1042/cs103s450s.
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Endothelins (ETs) participate directly and indirectly in angiogenesis via ET receptors. During early fetal angiogenesis, vascular endothelial growth factor (VEGF) and its receptors kinase insert domain-containing receptor (KDR) and fms-like tyrosine kinase-1 (Flt-1) are required for the development of the systemic vasculature. In late angiogenesis, stromal-cell-derived factor (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) act in an organ-specific manner to promote the formation and development of large blood vessels supplying the gastrointestinal tract. We studied the roles of these ligand receptors in angiogenesis during healing of gastric ulcers. We studied the following five groups, each consisting of ten cases of endoscopically confirmed gastric ulcer: active stage (GA), healing stage (GH) and scar stage (GS) of gastric ulcers located in the angulus; Helicobacter pylori (Hp)-positive gastritis (gast+); and Hp-negative gastritis (gast-). All cases in the ulcer groups were Hp-positive. The study materials consisted of frozen biopsy specimens of lesions arising in the angulus. ET-1 was measured by enzyme immunoassay. The other factors were assayed by reverse-transcription–PCR. The distributions of ET-1, ETA receptor (ETAR), SDF-1 and CXCR4 in the gastric mucosa were evaluated by enzyme immunoassay. ET-1 and ETAR reached peak levels during the GH (ET: P<0.05, ETAR: P<0.01). VEGF mRNA increased slightly during the GA, but did not differ significantly among the groups. KDR and Flt-1 levels were high during the GA, the level being significantly higher than those during the GH and GS (P<0.05). SDF-1 levels significantly decreased during the GH and GS compared with levels during the GA, and CXCR4 significantly increased during the GH and GS (P<0.01). On immunostaining, ET-1-positive cells and ETAR-positive cells were found in the endothelium, vascular smooth muscle and gastric epithelium, and CXCR4-positive cells were found in the endothelium and gastric epithelium during the GH and GS. Our results suggest that VEGF receptors are mainly expressed early in ulcer development and participate in the initial stage of angiogenesis. SDF-1 receptors and ETAR are primarily expressed during the GH and GS and are involved in vascular maturation and gastric mucosal regeneration during late angiogenesis.
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Tanha, K., S. R. Mahdavi, and G. Geraily. "Comparison of CCC and ETAR dose calculation algorithms in pituitary adenoma radiation treatment planning; Monte Carlo evaluation." Journal of Radiotherapy in Practice 13, no. 4 (May 28, 2014): 447–55. http://dx.doi.org/10.1017/s1460396914000211.
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AbstractAimsTo verify the accuracy of two common absorbed dose calculation algorithms in comparison to Monte Carlo (MC) simulation for the planning of the pituitary adenoma radiation treatment.Materials and methodsAfter validation of Linac's head modelling by MC in water phantom, it was verified in Rando phantom as a heterogeneous medium for pituitary gland irradiation. Then, equivalent tissue-air ratio (ETAR) and collapsed cone convolution (CCC) algorithms were compared for a conventional three small non-coplanar field technique. This technique uses 30 degree physical wedge and 18 MV photon beams.ResultsDose distribution findings showed significant difference between ETAR and CCC of delivered dose in pituitary irradiation. The differences between MC and dose calculation algorithms were 6.40 ± 3.44% for CCC and 10.36 ± 4.37% for ETAR. None of the algorithms could predict actual dose in air cavity areas in comparison to the MC method.ConclusionsDifference between calculation and true dose value affects radiation treatment outcome and normal tissue complication probability. It is of prime concern to select appropriate treatment planning system according to our clinical situation. It is further emphasised that MC can be the method of choice for clinical dose calculation algorithms verification.
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Agui, T., X. Xin, Y. Cai, T. Sakai, and K. Matsumoto. "Stimulation of interleukin-6 production by endothelin in rat bone marrow-derived stromal cells." Blood 84, no. 8 (October 15, 1994): 2531–38. http://dx.doi.org/10.1182/blood.v84.8.2531.2531.
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Abstract Endothelin (ET) produced by endothelial cells has recently been found to be a potent vasoconstricting hormone. In this report, ET is shown to be a potent stimulator of interleukin-6 (IL-6) production by rat bone marrow (BM)-derived stromal cells. It was also shown that ET increased the level of mRNA for IL-6 in these cells. The two types of ET receptor (R), ETAR and ETBR, were shown to be expressed on both BM-derived stromal cells in culture and ex vivo in BM tissue, suggesting that ET works as a physiologic stimulator of IL-6 production in the BM. It was shown that ETAR is coupled to phospholipase C activation, leading to the production of inositol 1,4,5-trisphosphate (IP3) and 1,2- diacylglycerol (DAG) as second messengers in BM-derived stromal cells. This was corroborated by data showing that IL-6 production in these cells was induced by combined stimulation with ionomycin and phorbol myristate acetate, thereby bypassing the effects of IP3 and DAG, respectively. This is the first report on the hormonal regulation of IL- 6 production by BM stromal cells, indicating that hematopoiesis is subject to endocrinologic regulation under physiologic conditions. ET has recently been reported to be produced by macrophages in response to bacterial lipopolysaccharide and human immunodeficiency virus-1 glycoprotein 120. These facts, taken together with our findings, raise the possibility that ET shares the same role of IL-1 as a local cytokine, mediating an intercellular signal between macrophages and BM stromal cells in response to bacterial or viral stimulation.
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Agui, T., X. Xin, Y. Cai, T. Sakai, and K. Matsumoto. "Stimulation of interleukin-6 production by endothelin in rat bone marrow-derived stromal cells." Blood 84, no. 8 (October 15, 1994): 2531–38. http://dx.doi.org/10.1182/blood.v84.8.2531.bloodjournal8482531.
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Endothelin (ET) produced by endothelial cells has recently been found to be a potent vasoconstricting hormone. In this report, ET is shown to be a potent stimulator of interleukin-6 (IL-6) production by rat bone marrow (BM)-derived stromal cells. It was also shown that ET increased the level of mRNA for IL-6 in these cells. The two types of ET receptor (R), ETAR and ETBR, were shown to be expressed on both BM-derived stromal cells in culture and ex vivo in BM tissue, suggesting that ET works as a physiologic stimulator of IL-6 production in the BM. It was shown that ETAR is coupled to phospholipase C activation, leading to the production of inositol 1,4,5-trisphosphate (IP3) and 1,2- diacylglycerol (DAG) as second messengers in BM-derived stromal cells. This was corroborated by data showing that IL-6 production in these cells was induced by combined stimulation with ionomycin and phorbol myristate acetate, thereby bypassing the effects of IP3 and DAG, respectively. This is the first report on the hormonal regulation of IL- 6 production by BM stromal cells, indicating that hematopoiesis is subject to endocrinologic regulation under physiologic conditions. ET has recently been reported to be produced by macrophages in response to bacterial lipopolysaccharide and human immunodeficiency virus-1 glycoprotein 120. These facts, taken together with our findings, raise the possibility that ET shares the same role of IL-1 as a local cytokine, mediating an intercellular signal between macrophages and BM stromal cells in response to bacterial or viral stimulation.
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Bagnato, Anna, Francesca Spinella, and Laura Rosanò. "The endothelin axis in cancer: the promise and the challenges of molecularly targeted therapyThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin." Canadian Journal of Physiology and Pharmacology 86, no. 8 (August 2008): 473–84. http://dx.doi.org/10.1139/y08-058.
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The endothelin (ET) axis, which includes ET-1, ET-2, ET-3, and 2 G protein-coupled receptor subtypes, ETAR and ETBR, promotes growth and progression of a variety of tumors, such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast, lung, bladder, endometrial carcinoma, Kaposi’s sarcoma, brain tumors, and melanoma. Acting on selective receptors, ET-1 regulates mitogenesis, cell survival, angiogenesis, bone remodeling, stimulation of nociceptors, tumor-infiltrating immune cells, epithelial-to-mesenchymal transition, invasion, and metastatic dissemination. At the molecular level, endothelin receptor antagonists, besides providing ideal tools for dissecting the ET axis, have demonstrated their potential in developing novel therapeutic strategies. Emerging experimental and clinical data demonstrate that interfering with endothelin receptors provides an opportunity for the development of rational combinatorial approaches using endothelin receptor antagonists in combination with chemotherapy or molecularly targeted therapy.
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Hudkins, Kelly L., Tomasz A. Wietecha, Floor Steegh, and Charles E. Alpers. "Beneficial effect on podocyte number in experimental diabetic nephropathy resulting from combined atrasentan and RAAS inhibition therapy." American Journal of Physiology-Renal Physiology 318, no. 5 (May 1, 2020): F1295—F1305. http://dx.doi.org/10.1152/ajprenal.00498.2019.
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Podocyte loss and proteinuria are both key features of human diabetic nephropathy (DN). The leptin-deficient BTBR mouse strain with the ob/ob mutation develops progressive weight gain, type 2 diabetes, and diabetic nephropathy that has many features of advanced human DN, including increased mesangial matrix, mesangiolysis, podocyte loss, and proteinuria. Selective antagonism of the endothelin-1 type A receptor (ETAR) by atrasentan treatment in combination with renin-angiotensin-aldosterone system inhibition with losartan has been shown to have the therapeutic benefit of lowering proteinuria in patients with DN, but the underlying mechanism for this benefit is not well understood. Using a similar therapeutic approach in diabetic BTBR ob/ob mice, this treatment regimen significantly increased glomerular podocyte number compared with diabetic BTBR ob/ob controls and suggested that parietal epithelial cells were a source for podocyte restoration. Atrasentan treatment alone also increased podocyte number but to a lesser degree. Mice treated with atrasentan demonstrated a reduction in proteinuria, matching the functional improvement reported in humans. This is a first demonstration that treatment with the highly selective ETAR antagonist atrasentan can lead to restoration of the diminished podocyte number characteristic of DN in humans and thereby underlies the reduction in proteinuria in patients with diabetes undergoing similar treatment. The benefit of ETAR antagonism in DN extended to a decrease in mesangial matrix as measured by a reduction in accumulations of collagen type IV in both the atrasentan and atrasentan + losartan-treated groups compared with untreated controls.
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Menino, Regina, Amélia Castelo-Branco, and José Casimiro Martins. "Lamas de ETAR: Aplicação em solos agro-florestais." Revista de Ciências Agrárias 41, no. 1 (January 2018): 52–55. http://dx.doi.org/10.19084/rca17227.
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Nowańska, Katarzyna, Mirosław Banasik, Piotr Donizy, Katarzyna Kościelska-Kasprzak, Sławomir Zmonarski, Krzysztof Letachowicz, Dorota Kamińska, et al. "Endothelin A Receptors Expressed in Glomeruli of Renal Transplant Patients May Be Associated with Antibody-Mediated Rejection." Journal of Clinical Medicine 10, no. 3 (January 22, 2021): 422. http://dx.doi.org/10.3390/jcm10030422.
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Background: Non-human leukocyte antigen (HLA) anti-endothelin A receptor antibodies are presented as being potentially important, but the expression of the endothelin A receptor in glomeruli (ETA receptor (g+)) has not yet been described. We decided to evaluate the presence and relevance of the ETA receptor in for-cause renal transplant biopsies. The aim of our study was to evaluate the immunoreactivity of the ETA receptor and its significance in patients who underwent a renal transplant biopsy due to the deterioration of transplant function, with detailed characterization of staining in glomeruli. Methods: The immunohistochemical expression of ETA receptor (ETAR) was analyzed in renal transplant biopsies. Microscopic evaluation was performed on paraffin sections in glomeruli. The analysis was performed using a two-step scale (0: lack of ETAR expression; 1: the presence of ETAR expression—mild to moderate immunoreactivity). Results: We analyzed 149 patients who underwent renal allograft biopsy after renal transplantation. Positive staining of ETA receptors in glomeruli (ETA receptor (g+)) was noticed in 13/149 (8.7%) patients. Five of these 13 (38.5%) patients with ETA receptor (g+) developed antibody-mediated rejection (AMR), while 13 of the remaining 136 (9.5%) ETA receptor (g-) patients developed AMR (p = 0.0022). Graft loss was noticed in all but one ETA receptor (g+) patient with AMR (4/5; 80%), but only in 2/13 (15%) ETA receptor (g-) patients with AMR (p = 0.009) during the first year after biopsy. Conclusions: The expression of endothelin A receptors in glomeruli seems to be a potentially important feature in the diagnosis of damage during antibody-mediated rejection. It may help to identify patients at a higher risk of allograft rejection and injury.