RESUMO
The endothelin family of peptides has long been recognized as a physiological regulator of diverse biological functions and mechanistically involved in various disease states, encompassing, among others, the cardiovascular system, the kidney, and the nervous system. Pharmacological blockade of the endothelin system, however, has encountered strong obstacles in its entry into the clinical mainstream, having obtained only a few proven indications until recently. This translational gap has been attributable predominantly to the relevant side effects associated with endothelin receptor antagonism (ERA), particularly fluid retention. Of recent, however, an expanding understanding of the pathophysiological processes involving endothelin, in conjunction with the development of new antagonists of endothelin receptors or adjustment of their doses, has driven a flourish of new clinical trials. The favorable results of some of them have extended the proven indications for ET targeting to a variety of clinical conditions, including resistant arterial hypertension and glomerulopathies. In addition, on the ground of strong preclinical evidence, other studies are ongoing to test the potential benefits of ERA in combination with other treatments, such as sodium-glucose co-transporter 2 inhibition in fluid retentive states or anti-cancer therapies in solid tumors. Furthermore, antibodies providing long-term blockade of endothelin receptors are under testing to overcome the short half-life of most small molecule endothelin antagonists. These efforts may yet bring new life to the translation of endothelin targeting strategies in clinical practice.
Assuntos
Antagonistas dos Receptores de Endotelina , Endotelinas , Humanos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Endotelinas/metabolismo , Animais , Receptores de Endotelina/metabolismoRESUMO
The tumor microenvironment (TME) plays a central role in the development of cancer. Within this complex milieu, the endothelin (ET) system plays a key role by triggering epithelial-to-mesenchymal transition, causing degradation of the extracellular matrix and modulating hypoxia response, cell proliferation, composition, and activation. These multiple effects of the ET system on cancer progression have prompted numerous preclinical studies targeting the ET system with promising results, leading to considerable optimism for subsequent clinical trials. However, these clinical trials have not lived up to the high expectations; in fact, the clinical trials have failed to demonstrate any substantiated benefit of targeting the ET system in cancer patients. This review discusses the major and recent advances of the ET system with respect to TME and comments on past and ongoing clinical trials of the ET system.
Assuntos
Endotelinas , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/patologia , Neoplasias/metabolismo , Endotelinas/metabolismo , Endotelinas/fisiologia , Animais , Transição Epitelial-Mesenquimal , Transdução de SinaisRESUMO
Retinitis pigmentosa (RP) and macular dystrophy (MD) cause severe retinal dysfunction, affecting 1 in 4000 people worldwide. This disease is currently assumed to be intractable, because effective therapeutic methods have not been established, regardless of genetic or sporadic traits. Here, we examined a RP mouse model in which the Prominin-1 (Prom1) gene was deficient and investigated the molecular events occurring at the outset of retinal dysfunction. We extracted the Prom1-deficient retina subjected to light exposure for a short time, conducted single-cell expression profiling, and compared the gene expression with and without stimuli. We identified the cells and genes whose expression levels change directly in response to light stimuli. Among the genes altered by light stimulation, Igf1 was decreased in rod photoreceptor cells and astrocytes under the light-stimulated condition. Consistently, the insulin-like growth factor (IGF) signal was weakened in light-stimulated photoreceptor cells. The recovery of Igf1 expression with the adeno-associated virus (AAV) prevented photoreceptor cell death, and its treatment in combination with the endothelin receptor antagonist led to the blockade of abnormal glial activation and the promotion of glycolysis, thereby resulting in the improvement of retinal functions, as assayed by electroretinography. We additionally demonstrated that the attenuation of mammalian/mechanistic target of rapamycin (mTOR), which mediates IGF signalling, leads to complications in maintaining retinal homeostasis. Together, we propose that combinatorial manipulation of distinct mechanisms is useful for the maintenance of the retinal condition.
Assuntos
Degeneração Macular , Doenças Retinianas , Retinose Pigmentar , Animais , Camundongos , Endotelinas , Fator de Crescimento Insulin-Like I/genética , Retina , Células Fotorreceptoras Retinianas BastonetesRESUMO
This study investigated the modulatory effect of Ginkgo biloba extract on lead acetate-induced endothelial dysfunction. Animals were administered GBE (50 mg/kg and 100 mg/kg orally) after exposures to lead acetate (25 mg/kg orally) for 14 days. Aorta was harvested after euthanasia, the tissue was homogenised, and supernatants were decanted after centrifuging. Oxidative, nitrergic, inflammatory, and anti-apoptotic markers were assayed using standard biochemical procedure, ELISA, and immunohistochemistry, respectively. GBE reduced lead-induced oxidative stress by increasing SOD, GSH, and CAT as well as reducing MDA levels in endothelium. Pro-inflammatory cytokines (TNF-α and IL-6) were reduced while increasing Bcl-2 protein expression. GBE lowered endothelin-I and raised nitrite levels. Histological changes caused by lead acetate were normalised by GBE. Our findings suggest that Ginkgo biloba extract restored endothelin-I and nitric oxide functions by increasing Bcl-2 protein expression and reducing oxido-inflammatory stress in endothelium.
Assuntos
Extrato de Ginkgo , Ginkgo biloba , Chumbo , Ratos , Animais , Extratos Vegetais/farmacologia , Endotelinas , Proteínas Proto-Oncogênicas c-bcl-2 , AcetatosRESUMO
ET (endothelin) is a powerful vasoconstrictor 21-amino acid peptide present in many tissues, which exerts many physiological functions across the body and participates as a mediator in many pathological conditions. ETs exert their effects through ETA and ETB receptors, which can be blocked by selective receptor antagonists. ETs were shown to play important roles among others, in systemic hypertension, particularly when resistant or difficult to control, and in pulmonary hypertension, atherosclerosis, cardiac hypertrophy, subarachnoid hemorrhage, chronic kidney disease, diabetic cardiovascular disease, scleroderma, some cancers, etc. To date, ET antagonists are only approved for the treatment of primary pulmonary hypertension and recently for IgA nephropathy and used in the treatment of digital ulcers in scleroderma. However, they may soon be approved for the treatment of patients with resistant hypertension and different types of nephropathy. Here, the role of ETs is reviewed with a special emphasis on participation in and treatment of hypertension and chronic kidney disease.
Assuntos
Hipertensão Pulmonar , Hipertensão , Insuficiência Renal Crônica , Humanos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Endotelinas , Hipertensão/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Endotelina-1/fisiologia , Receptores de Endotelina , Receptor de Endotelina ARESUMO
Endothelins and their receptors, type A (ETA) and type B (ETB), modulate vital cellular processes, including growth, survival, invasion and angiogenesis, through multiple G proteins. This review highlights the structural determinations of these receptors by X-ray crystallography and cryo-electron microscopy, and their activation mechanisms by endothelins. Explorations of the conformational changes upon receptor activation have provided insights into the unique G-protein coupling feature of the endothelin receptors. The review further delves into the binding modes of the clinical antagonist and the inverse agonists. These findings significantly contribute to understanding the mechanism of G-protein activation and have potential implications for drug development, particularly in the context of vasodilatory antagonists and agonists targeting the endothelin receptors.
Assuntos
Agonismo Inverso de Drogas , Endotelinas , Microscopia Crioeletrônica , Endotelinas/metabolismo , Receptores de Endotelina/química , Receptores de Endotelina/metabolismo , Transdução de SinaisRESUMO
BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) leads to ductular reaction and fibrosis and is complicated by vascular dysfunction. Cholangiocyte and endothelial cell crosstalk modulates their proliferation in cholestatic models. Endothelin (ET)-1 and ET-2 bind to their receptor, ET-A, and cholangiocytes are a key source of ET-1 after bile duct ligation. We aimed to evaluate the therapeutic potential of ET-A inhibition in PSC and biliary-endothelial crosstalk mediated by this pathway. METHODS: Wild-type and multidrug resistance 2 knockout (Mdr2-/-) mice at 12 weeks of age were treated with vehicle or Ambrisentan (ET-A antagonist) for 1 week by daily intraperitoneal injections. Human control and PSC samples were used. RESULTS: Mdr2-/- mice at 4, 8, and 12 weeks displayed angiogenesis that peaked at 12 weeks. Mdr2-/- mice at 12 weeks had enhanced biliary ET-1/ET-2/ET-A expression and secretion, whereas human PSC had enhanced ET-1/ET-A expression and secretion. Ambrisentan reduced biliary damage, immune cell infiltration, and fibrosis in Mdr2-/- mice. Mdr2-/- mice had squamous cholangiocytes with blunted microvilli and dilated arterioles lacking cilia; however, Ambrisentan reversed these alterations. Ambrisentan decreased cholangiocyte expression of pro-angiogenic factors, specifically midkine, through the regulation of cFOS. In vitro, ET-1/ET-A caused cholangiocyte senescence, endothelial cell angiogenesis, and macrophage inflammation. In vitro, human PSC cholangiocyte supernatants increased endothelial cell migration, which was blocked with Ambrisentan treatment. CONCLUSIONS: ET-A inhibition reduced biliary and liver damage in Mdr2-/- mice. ET-A promotes biliary angiocrine signaling that may, in turn, enhance angiogenesis. Targeting ET-A may prove therapeutic for PSC, specifically patients displaying vascular dysfunction.
Assuntos
Colangite Esclerosante , Colangite , Humanos , Camundongos , Animais , Recém-Nascido , Colangite Esclerosante/tratamento farmacológico , Colangite Esclerosante/metabolismo , Receptores de Endotelina/uso terapêutico , Camundongos Knockout , Cirrose Hepática/metabolismo , Fibrose , Endotelinas/uso terapêuticoRESUMO
The endothelin (ET) signaling system is comprised of three endothelin peptides (ET-1, -2 and -3) and two corresponding endothelin-A and -B receptors (ETAR and ETBR), which belong to the G-protein coupled receptor (GPCR) superfamily. The endothelin axis, as this system is also referred to, contributes to the maintenance of vascular tone, functions as regulator of inflammation and proliferation and helps in balancing water homeostasis. In pathological settings, the ET axis is known to contribute to endothelial activation in cardiovascular diseases, to cell proliferation, chemoresistance and metastasis in cancer and to inflammation and fibrosis in renal disease. Antagonists of ETAR and ETBR, either subtype-specific compounds or substances with high affinity to both receptors, have been developed for more than 30 years. In the preclinical context, in vivo imaging of endothelin receptor expression has been utilized to assess ET-axis contribution to e.g. cancer or myocardial infarction. In this work, we present the development and synthesis of two novel ETBR-specific fluorescent probes, based on the available antagonists BQ788 and IRL2500 and their preliminary evaluation in a breast cancer context.
Assuntos
Neoplasias da Mama , Corantes Fluorescentes , Feminino , Humanos , Neoplasias da Mama/metabolismo , Endotelinas , Inflamação , Receptor de Endotelina A/metabolismoRESUMO
The endothelin ETB receptor is a promiscuous G-protein coupled receptor that is activated by vasoactive peptide endothelins. ETB signaling induces reactive astrocytes in the brain and vasorelaxation in vascular smooth muscle. Consequently, ETB agonists are expected to be drugs for neuroprotection and improved anti-tumor drug delivery. Here, we report the cryo-electron microscopy structure of the endothelin-1-ETB-Gi complex at 2.8 Å resolution, with complex assembly stabilized by a newly established method. Comparisons with the inactive ETB receptor structures revealed how endothelin-1 activates the ETB receptor. The NPxxY motif, essential for G-protein activation, is not conserved in ETB, resulting in a unique structural change upon G-protein activation. Compared with other GPCR-G-protein complexes, ETB binds Gi in the shallowest position, further expanding the diversity of G-protein binding modes. This structural information will facilitate the elucidation of G-protein activation and the rational design of ETB agonists.
Assuntos
Endotelina-1 , Endotelinas , Endotelina-1/metabolismo , Microscopia Crioeletrônica , Receptor de Endotelina B/metabolismo , Endotelinas/metabolismo , Proteínas de Ligação ao GTP/metabolismoRESUMO
PURPOSE: Changes in the activity of endothelins and their receptors may promote neoplastic processes. They can be caused by epigenetic modifications and modulators, but little is known about endothelin-3 (EDN3), particularly in endometrial cancer. The aim of the study was to determine the expression profile of endothelin family and their interactions with miRNAs, and to assess the degree of EDN3 methylation. METHODS: The study enrolled 45 patients with endometrioid endometrial cancer and 30 patients without neoplastic changes. The expression profile of endothelins and their receptors was determined with mRNA microarrays and RT-qPCR. The miRNA prediction was based on the miRNA microarray experiment and the mirDB tool. The degree of EDN3 methylation was assessed by MSP. RESULTS: EDN1 and EDNRA were overexpressed regardless of endometrial cancer grade, which may be due to the lack of regulatory effect of miR-130a-3p and miR-485-3p, respectively. In addition, EDN3 and EDNRB were significantly downregulated. CONCLUSION: The endothelial axis is disturbed in endometrioid endometrial cancer. The observed silencing of EDN3 activity may be mainly due to DNA methylation.
Assuntos
Carcinoma Endometrioide , Neoplasias do Endométrio , MicroRNAs , Feminino , Humanos , Endotelina-3/genética , Endotelina-3/metabolismo , Endotelinas/genética , Endotelinas/metabolismo , MicroRNAs/genética , Receptor de Endotelina A/genética , Neoplasias do Endométrio/genética , Carcinoma Endometrioide/genética , Regulação Neoplásica da Expressão Gênica , Endotelina-1/genética , Endotelina-1/metabolismoRESUMO
Purpose: To investigate the role of hypoxia-inducible transcription factor-1 alpha (HIF-1α) and angiogenetic factor endothelin-1 (ET-1) expression in regulating hypoxia and placental development by routine histopathological methods. Methods: Twenty preeclamptic and normal placentas were used. Placenta tissue pieces were examined histopathologically after routine paraffin follow-ups. HIF-1α and ET-1 proteins were examined immunohistochemically, and placental tissues were examined ultrastructurally. Results: Increase in syncytial proliferation, endothelial damage in vessels, and increase in collagen were observed in preeclamptic placentas. As a result of preeclampsia, an increase was observed in HIF-1α and ET-1 protein levels in the placenta. Dilatation of endoplasmic reticulum and loss of cristae in mitochondria were observed in trophoblast cells in preeclamptic placental sections. Conclusion: High regulation of oxygen resulting from preeclampsia has been shown to be a critical determinant of placentagenesis and plays an important role in placental differentiation, changes in maternal and fetal blood circulation, trophoblastic invasion, and syncytial node increase. It has been thought that preeclampsia affects secretion by disrupting the endoplasmic reticulum structure and induces mitochondrial damage, and that ET-1 may potentially help in the induction of stress pathways as a result of hypoxia in preeclampsia.
Assuntos
Placenta/fisiopatologia , Doenças Placentárias , Pré-Eclâmpsia , Endotelinas , Subunidade alfa do Fator 1 Induzível por Hipóxia , Imuno-HistoquímicaRESUMO
Purpose: Glaucoma is a neurodegenerative disease associated with elevated intraocular pressure and characterized by optic nerve axonal degeneration, cupping of the optic disc, and loss of retinal ganglion cells (RGCs). The endothelin (ET) system of vasoactive peptides (ET-1, ET-2, ET-3) and their G-protein coupled receptors (ETA and ETB receptors) have been shown to contribute to the pathophysiology of glaucoma. The purpose of this study was to determine whether administration of the endothelin receptor antagonist macitentan was neuroprotective to RGCs and optic nerve axons when administered after the onset of intraocular pressure (IOP) elevation in ocular hypertensive rats. Methods: Male and female Brown Norway rats were subjected to the Morrison model of ocular hypertension by injection of hypertonic saline through the episcleral veins. Following IOP elevation, macitentan (5 mg/kg body wt) was administered orally 3 days per week, and rats with IOP elevation were maintained for 4 weeks. RGC function was determined by pattern electroretinography (PERG) at 2 and 4 weeks post-IOP elevation. Rats were euthanized by approved humane methods, and retinal flat mounts were generated and immunostained for the RGC-selective marker Brn3a. PPD-stained optic nerve sections were imaged by confocal microscopy. RGC and axon counts were conducted in a masked manner and compared between the treatment groups. Results: Significant protection against loss of RGCs and optic nerve axons was found following oral administration of macitentan in rats with elevated IOP. In addition, a protective trend for RGC function, as measured by pattern ERG analysis, was evident following macitentan treatment. Conclusions: Macitentan treatment had a neuroprotective effect on RGCs and their axons, independent of its IOP-lowering effect, suggesting that macitentan may complement existing treatments to prevent neurodegeneration during ocular hypertension. The findings presented have implications for the use of macitentan as an oral formulation to promote neuroprotection in glaucoma patients.
Assuntos
Glaucoma , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Hipertensão Ocular , Masculino , Feminino , Ratos , Animais , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Roedores , Antagonistas dos Receptores de Endotelina/farmacologia , Modelos Animais de Doenças , Glaucoma/complicações , Glaucoma/tratamento farmacológico , Pressão Intraocular , Hipertensão Ocular/complicações , Hipertensão Ocular/tratamento farmacológico , Ratos Endogâmicos BN , Axônios , Endotelinas/farmacologia , Administração Oral , Peptídeos/farmacologiaRESUMO
Fibrocytes are bone marrow-derived monocytic cells implicated in wound healing. Here, we identify their role in lung cancer progression/ metastasis. Selective manipulation of fibrocytes in mouse lung tumor models documents the central role of fibrocytes in boosting niche features and enhancing metastasis. Importantly, lung cancer patients show increased number of circulating fibrocytes and marked fibrocyte accumulation in the cancer niche. Using double and triple co-culture systems with human lung cancer cells, fibrocytes, macrophages and endothelial cells, we substantiate the central features of cancer-supporting niche: enhanced cancer cell proliferation and migration, macrophage activation, augmented endothelial cell sprouting and fibrocyte maturation. Upregulation of endothelin and its receptors are noted, and dual endothelin receptor blockade suppresses all cancer-supportive phenotypic alterations via acting on fibrocyte interaction with the cancer niche. We thus provide evidence for a crucial role of fibrocytes in lung cancer progression and metastasis, suggesting targets for treatment strategies.
Assuntos
Células Endoteliais , Neoplasias Pulmonares , Animais , Endotelinas , Fibroblastos/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Monócitos/patologia , Receptores de EndotelinaRESUMO
COVID19 patients with severe infection have been observed to have elevated autoantibodies (AAs) against angiotensin II receptor type 1 (AT1R) and endothelin (ET) 1 receptor type A (ETAR), compared with healthy controls and patients with favorable (mild) infection. AT1R and ETAR are G proteincoupled receptors, located on vascular smooth muscle cells, fibroblasts, immune and endothelial cells, and are activated by angiotensin II (Ang II) and ET1 respectively. AAs that are specific for these receptors have a functional role similar to the natural ligands, but with a more prolonged vasoconstrictive effect. They also induce the production of fibroblast collagen, the release of reactive oxygen species and the secretion of proinflammatory cytokines (including IL6, IL8 and TNFα) by immune cells. Despite the presence of AAs in severe COVID19 infected patients, their contribution and implication in the severity of the disease is still not well understood and further studies are warranted. The present review described the major vascular homeostasis systems [ET and reninangiotensinaldosterone system (RAAS)], the vital regulative role of nitric oxide, the AAs, and finally the administration of angiotensin II receptor blockers (ARBs), so as to provide more insight into the interplay that exists among these components and their contribution to the severity, prognosis and possible treatment of COVID19.
Assuntos
COVID-19 , Doenças Vasculares , Angiotensina II , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Colágeno , Células Endoteliais , Endotelinas , Humanos , Interleucina-6 , Interleucina-8 , Óxido Nítrico , Espécies Reativas de Oxigênio , Receptor Tipo 1 de Angiotensina , Receptor de Endotelina A , Receptores de Angiotensina , Fator de Necrose Tumoral alfaRESUMO
The development of essential hypertension involves several factors. Vascular dysfunction, characterized by endothelial dysfunction, low-grade inflammation and structural remodeling, plays an important role in the initiation and maintenance of essential hypertension. Although the mechanistic pathways by which essential hypertension develops are poorly understood, several pharmacological classes available on the clinical settings improve blood pressure by interfering in the cardiac output and/or vascular function. This review is divided in two major sections. The first section depicts the major molecular pathways as renin angiotensin aldosterone system (RAAS), endothelin, nitric oxide signalling pathway and oxidative stress in the development of vascular dysfunction. The second section describes the role of some pharmacological classes such as i) RAAS inhibitors, ii) dual angiotensin receptor-neprilysin inhibitors, iii) endothelin-1 receptor antagonists, iv) soluble guanylate cyclase modulators, v) phosphodiesterase type 5 inhibitors and vi) sodium-glucose cotransporter 2 inhibitors in the context of hypertension. Some classes are already approved in the treatment of hypertension, but others are not yet approved. However, due to their potential benefits these classes were included.
Assuntos
Anti-Hipertensivos , Hipertensão , Humanos , Anti-Hipertensivos/farmacologia , Músculo Liso Vascular/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Neprilisina/metabolismo , Óxido Nítrico/metabolismo , Hipertensão Essencial/tratamento farmacológico , Hipertensão Essencial/metabolismo , Inibidores da Fosfodiesterase 5/uso terapêutico , Receptor de Endotelina A/metabolismo , Hipertensão/metabolismo , Sistema Renina-Angiotensina , Endotelinas/metabolismo , Endotelinas/farmacologia , Endotelinas/uso terapêutico , Antagonistas dos Receptores de Endotelina/farmacologia , Receptores de Angiotensina/metabolismo , Receptores de Angiotensina/uso terapêutico , Glucose/metabolismo , Sódio/metabolismo , Sódio/farmacologia , Sódio/uso terapêuticoRESUMO
BACKGROUND: Feminizing hormonal therapy (FHT) and HIV potentially alter cardiovascular disease (CVD) risk in transgender women (TW). METHODS: TW were enrolled in Los Angeles, California and Houston, Texas and frequency-matched to Multicenter AIDS Cohort Study cisgender men (CM) on age, race, substance use, and abacavir use. Biomarkers of CVD risk and inflammation were assessed via ELISA. Wilcoxon rank sum and Fisher's exact tests compared TW and CM. Multivariable linear regression assessed factors associated with biomarker concentrations. RESULTS: TW (HIV+ n â=â75, HIV- n â=â47) and CM (HIV+ n â=â40, HIV- n â=â40) had mean age 43-45âyears; TW/CM were 90%/91% non-Hispanic Black, Hispanic, or Multiracial, 26%/53% obese, and 34%/24% current smokers; 67% of TW were on FHT. Among people with HIV (PWH), TW had higher median extracellular newly-identified receptor for advanced glycation end-products (EN-RAGE), lipoprotein-associated phospholipase A2 (LpPLA2), oxidized low-density lipoprotein (oxLDL), soluble tumor necrosis factor receptor type (sTNFR) I/II, interleukin (IL)-8 and plasminogen activator inhibitor (PAI)-1, but lower soluble CD14, von Willebrand factor (vWF) and endothelin (ET)-1 levels than CM. Findings were similar for participants without HIV (all P â<â0.05). In multivariable analysis, TW had higher EN-RAGE, IL-6, IL-8, P selectin, PAI-1, oxLDL and sTNFRI/II concentrations, and lower vWF, independent of HIV serostatus and current FHT use. Both being a TW and a PWH were associated with lower ET-1. CONCLUSIONS: Compared to matched cisgender men, trans women have altered profiles of biomarkers associated with systemic inflammation and CVD. Further work is needed to decipher the contributions of FHT to CVD risk in TW with HIV.
Assuntos
Doenças Cardiovasculares , Infecções por HIV , 1-Alquil-2-acetilglicerofosfocolina Esterase , Adulto , Biomarcadores , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Endotelinas , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Hormônios , Humanos , Inflamação , Interleucina-6 , Interleucina-8 , Receptores de Lipopolissacarídeos , Lipoproteínas LDL , Masculino , Pessoa de Meia-Idade , Selectina-P , Inibidor 1 de Ativador de Plasminogênio , Receptor para Produtos Finais de Glicação Avançada , Fator de von WillebrandRESUMO
Delivery of therapeutic agents in pancreatic cancer (PC) is impaired due to its hypovascular and desmoplastic tumor microenvironment. The Endothelin (ET)-axis is the major regulator of vasomotor tone under physiological conditions and is highly upregulated in multiple cancers. We investigated the effect of dual endothelin receptor antagonist bosentan on perfusion and macromolecular transport in a PC cell-fibroblast co-implantation tumor model using Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI). Following bosentan treatment, the contrast enhancement ratio and wash-in rates in tumors were two- and nine times higher, respectively, compared to the controls, whereas the time to peak was significantly shorter (7.29 ± 1.29 min v/s 22.08 ± 5.88 min; p = 0.04). Importantly, these effects were tumor selective as the magnitudes of change for these parameters were much lower in muscles. Bosentan treatment also reduced desmoplasia and improved intratumoral distribution of high molecular weight FITC-dextran. Overall, these findings support that targeting the ET-axis can serve as a potential strategy to selectively enhance tumor perfusion and improve the delivery of therapeutic agents in pancreatic tumors.
Assuntos
Antagonistas dos Receptores de Endotelina , Neoplasias Pancreáticas , Bosentana , Antagonistas dos Receptores de Endotelina/farmacologia , Antagonistas dos Receptores de Endotelina/uso terapêutico , Endotelinas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Perfusão , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
BACKGROUND: Fibrosis is defined as an excessive accumulation of extracellular matrix (ECM) components. Many organs are subjected to fibrosis including the lung, liver, heart, skin, kidney, and muscle. Muscle fibrosis occurs in response to trauma, aging, or dystrophies and impairs muscle function. Fibrosis represents a hurdle for the treatment of human muscular dystrophies. While data on the mechanisms of fibrosis have mostly been investigated in mice, dystrophic mouse models often do not recapitulate fibrosis as observed in human patients. Consequently, the cellular and molecular mechanisms that lead to fibrosis in human muscle still need to be identified. METHODS: Combining mass cytometry, transcriptome profiling, in vitro co-culture experiments, and in vivo transplantation in immunodeficient mice, we investigated the role and nature of nonmyogenic cells (fibroadipogenic progenitors, FAPs) from human fibrotic muscles of healthy individuals (FibMCT ) and individuals with oculopharyngeal muscular dystrophy (OPMD; FibMOP ), as compared with nonmyogenic cells from human nonfibrotic muscle (MCT ). RESULTS: We found that the proliferation rate of FAPs from fibrotic muscle is 3-4 times higher than those of FAPs from nonfibrotic muscle (population doubling per day: MCT 0.2 ± 0.1, FibMCT 0.7 ± 0.1, and FibMOP 0.8 ± 0.3). When cocultured with muscle cells, FAPs from fibrotic muscle impair the fusion index unlike MCT FAPs (myoblasts alone 57.3 ± 11.1%, coculture with MCT 43.1 ± 8.9%, with FibMCT 31.7 ± 8.2%, and with FibMOP 36.06 ± 10.29%). We also observed an increased proliferation of FAPs from fibrotic muscles in these co-cultures in differentiation conditions (FibMCT +17.4%, P < 0.01 and FibMOP +15.1%, P < 0.01). This effect is likely linked to the increased activation of the canonical TGFß-SMAD pathway in FAPs from fibrotic muscles evidenced by pSMAD3 immunostaining (P < 0.05). In addition to the profibrogenic TGFß pathway, we identified endothelin as a new actor implicated in the altered cross-talk between muscle cells and fibrotic FAPs, confirmed by an improvement of the fusion index in the presence of bosentan, an endothelin receptor antagonist (from 33.8 ± 10.9% to 52.9 ± 10.1%, P < 0.05). CONCLUSIONS: Our data demonstrate the key role of FAPs and their cross-talk with muscle cells through a paracrine signalling pathway in fibrosis of human skeletal muscle and identify endothelin as a new druggable target to counteract human muscle fibrosis.
Assuntos
Adipogenia , Distrofia Muscular Oculofaríngea , Animais , Endotelinas/metabolismo , Retroalimentação , Fibrose , Humanos , Camundongos , Fibras Musculares Esqueléticas , Músculo Esquelético/patologia , Distrofia Muscular Oculofaríngea/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Although endothelin receptor type A (ETA) is emerging as a novel anticancer target, previously only small molecule drugs have been available as ETA antagonists. Ju and colleagues have successfully developed a functional anti-ETA antibody for colorectal cancer.
Assuntos
Endotelinas , Neoplasias , Anticorpos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Receptor de Endotelina ARESUMO
Therapeutic hypothermia with modest results is the only treatment currently available for neonatal hypoxic ischemic encephalopathy (HIE). Endothelin B (ETB) receptors in the brain are shown to have neural restorative capacity. ETB receptors agonist sovateltide alone or as an adjuvant therapy may enhance neurovascular remodeling in HIE. Sprague-Dawley rat pups were grouped based on treatments into (1) Control; (2) HIE + Vehicle; (3) HIE + Hypothermia; (4) HIE + sovateltide; and (5) HIE + sovateltide + hypothermia. HIE was induced on postnatal day (PND) 7, followed by sovateltide (5 µg/kg) intracerebroventricular injection and/or hypothermia. On PND 10, brains were analyzed for the expression of vascular endothelial growth factor (VEGF), nerve growth factor (NGF), ETB receptors, oxidative stress and cellular damage markers. Vehicle-treated animals had high oxidative stress level as indicated by an increase in lipid peroxidation factor, malondialdehyde, and decreased antioxidants, reduced glutathione and superoxide dismutase, compared to control. These effects were reversed in sovateltide alone (p < 0.001) or in combination with the therapeutic hypothermia (p < 0.001), indicating that ETB receptor activation reduces oxidative stress injury following HIE. Animals receiving sovateltide demonstrated a significant (p < 0.0001) upregulation of ETB receptor, VEGF, and NGF expression in the brain compared to vehicle-treated animals. Additionally, sovateltide alone or in combination with therapeutic hypothermia significantly (p < 0.001) reduced cell death when compared to vehicle or therapeutic hypothermia alone, demonstrating that sovateltide is neuroprotective and attenuates neural damage following HIE. These findings are important and merit additional studies for development of new interventions for improving neurodevelopmental outcomes after HIE.