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1.
Prostaglandins Other Lipid Mediat ; 143: 106343, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31195125

RESUMO

Prostaglandins (PGs) play a pivotal role in uterine reproductive process including maternal recognition of pregnancy, cell proliferation, and myometrium contractions in mammals. In this study, we investigated the immunolocalizations and expression levels of Prostaglandin E2 synthases cyclo-oxygenase (COX)-1 and COX-2, as well as one of PGE2 receptor subtypes 4 (EP4) in the uteri of the wild Daurian ground squirrels (Spermophilus dauricus) during the breeding and non-breeding seasons. Histologically, the thickness of endometrium: myometrium ratio in the uteri of the breeding season was higher than that of the non-breeding season. The immunostainings of COX-1, COX-2 and EP4 were observed in stromal cells, glandular cells and myometrium cells in the breeding and non-breeding seasons. The protein and mRNA expression levels of COX-1, COX-2 and EP4 were higher in the uteri of the breeding season than those of in the non-breeding season. The mean mRNA levels of COX-1, COX-2 and EP4 were positively correlated with uterine weights. In addition, the PGE2 concentration of uterine tissues as well as plasma PGE2, 17ß-estradiol, progesterone, LH and FSH levels were also significantly higher in the breeding season compared to those of the non-breeding season. These results suggested that PGE2 might play an important autocrine or paracrine role in the regulation of seasonal changes in the uterine functions of the wild Daurian ground squirrels during the breeding and non-breeding seasons.


Assuntos
Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Regulação Enzimológica da Expressão Gênica , Receptores de Prostaglandina E Subtipo EP4/genética , Sciuridae/genética , Estações do Ano , Animais , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/sangue , Dinoprostona/metabolismo , Feminino , Tamanho do Órgão , Transporte Proteico , RNA Mensageiro/genética , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Sciuridae/anatomia & histologia , Útero/anatomia & histologia , Útero/citologia , Útero/metabolismo
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(4): 357-361, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31167696

RESUMO

Objective To investigate the clinical significance of plasma cell free DNA (cfDNA) methylation in short stature homeobox 2 (SHOX2) and prostaglandin E receptor 4 (PTGER4) for diagnosing pulmonary nodule patients. Methods We collected 10 mL venous blood from patients. And the plasma DNA was extracted. Real-time quantitative PCR was performed to amplify the DNA after bisulfite conversion. Valid Ct values were input into specialized software to analyze the methylation status of SHOX2 and PTGER4. Histological classification of lung malignant tissues was carried out by immunohistochemistry. Results The 22 of 57 patients were positive and 35 were negative for SHOX2 and PTGER4 DNA methylation detection. Computed tomography (CT) indicated that 31 of 57 patients were diagnosed with pulmonary nodules, among which 19 patients were positive for DNA methylation; 3 of 16 patients with inflammation on CT were positive for DNA methylation; 10 patients with normal or ground glass CT images were negative for DNA methylation. Significant differences in SHOX2 and PTGER4 DNA methylation were observed in the patients with different CT findings. The highest positive rate of CT nodular lesions was 61.3%. The 20 patients with pulmonary nodules were pathologically diagnosed with lung cancer, of which 18 were positive for SHOX2 and PTGER4 DNA methylation, with a positive rate of 90%. Only 1 case of benign pulmonary nodules was positive. Significant difference in SHOX2 and PTGER4 methylation status was observed between benign and malignant pulmonary nodules. The positive rate of SHOX2 and PTGER4 methylation were both 100% in squamous cell lung carcinoma and small cell lung carcinoma, while 75% in adenocarcinoma. Conclusion SHOX2 and PTGER4 methylation detection in blood plasma has certain value in the early diagnosis of lung cancer and can be a complementary tool of CT in diagnosing pulmonary nodule patients.


Assuntos
Metilação de DNA , Proteínas de Homeodomínio/genética , Neoplasias Pulmonares/diagnóstico , Receptores de Prostaglandina E Subtipo EP4/genética , Biomarcadores Tumorais , Diagnóstico Diferencial , Proteínas de Homeodomínio/sangue , Humanos , Neoplasias Pulmonares/genética , Receptores de Prostaglandina E Subtipo EP4/sangue
3.
Toxicol In Vitro ; 60: 400-411, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31247335

RESUMO

Neuronal exposure to 6-hydroxydopamine (6-OHDA), a hydroxylated analog of dopamine, constitutes a very useful strategy for studying the molecular events associated with neuronal death in Parkinson's disease. 6-OHDA increases oxidant levels and impairs mitochondrial respiratory chain, thus promoting neuronal injury and death. Despite the extensive use of 6-OHDA in animal models, the exact molecular events triggered by this neurotoxicant at the neuronal level have not been yet fully understood. Human IMR-32 neuroblastoma cells exposed to increasing concentrations of 6-OHDA displayed high levels of reactive oxygen species and increased plasma membrane permeability with concomitant cell viability diminution. As part of the neuronal response to 6-OHDA exposure, the nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) p65 subunit was observed. NFκB nuclear localization was also accompanied by an increase of IκB phosphorylation as well as a rise in cyclooxygenase-2 (COX-2) and the prostaglandin receptor, EP4, mRNA levels. Even though the canonical pathways participating in the modulation of NFκB have been extensively described, here we tested the hypothesis that 6-OHDA-induced injury can activate lipid signaling and, in turn, modulate the transcriptional response. 6-OHDA challenge triggered the activation of lipid signaling pathways and increased phosphatidic acid (PA), diacylglycerol and free fatty acid levels in human neuroblastoma cells. The inhibition of PA production was able to prevent the decrease in cell viability triggered by 6-OHDA, the nuclear translocation of NFκB p65 subunit and the rise in COX-2 mRNA expression. Our results indicate that the onset of the inflammatory process triggered by 6-OHDA involves the activation of PA signaling that, in turn, governs NFκB subcellular localization and COX-2 expression.


Assuntos
Adrenérgicos/toxicidade , NF-kappa B/metabolismo , Oxidopamina/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Dopamina/metabolismo , Humanos , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas , Receptores de Prostaglandina E Subtipo EP4/genética
4.
Nat Commun ; 10(1): 1888, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015404

RESUMO

The use of nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX)-1 and COX-2, increases heart failure risk. It is unknown whether microsomal (m) prostaglandin (PG) E synthase (S)-1, a target downstream of COX, regulates myocardial (M) ischemia/reperfusion (I/R) injury, a key determinant of heart failure. Here we report that COX-1 and mPGES-1 mediate production of substantial amounts of PGE2 and confer cardiac protection in MI/R. Deletion of mPges-1 impairs cardiac microvascular perfusion and increases inflammatory cell infiltration in mouse MI/R. Consistently, mPges-1 deletion depresses the arteriolar dilatory response to I/R in vivo and to acetylcholine ex vivo, and enhances leukocyte-endothelial cell interaction, which is mediated via PGE receptor-4 (EP4). Furthermore, endothelium-restricted Ep4 deletion impairs microcirculation, and exacerbates MI/R injury, irrespective of EP4 agonism. Treatment with misoprostol, a clinically available PGE analogue, improves microcirculation and reduces MI/R injury. Thus, mPGES-1, a key microcirculation protector, constrains MI/R injury and this beneficial effect is partially mediated via endothelial EP4.


Assuntos
Vasos Coronários/patologia , Ciclo-Oxigenase 1/metabolismo , Proteínas de Membrana/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Prostaglandina-E Sintases/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Animais , Ciclo-Oxigenase 1/genética , Dinoprostona/metabolismo , Modelos Animais de Doenças , Endotélio/patologia , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microcirculação/efeitos dos fármacos , Misoprostol/farmacologia , Misoprostol/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/etiologia , Miocárdio/patologia , Prostaglandina-E Sintases/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Transdução de Sinais
5.
Nat Commun ; 10(1): 181, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30643142

RESUMO

Whether sensory nerve can sense bone density or metabolic activity to control bone homeostasis is unknown. Here we found prostaglandin E2 (PGE2) secreted by osteoblastic cells activates PGE2 receptor 4 (EP4) in sensory nerves to regulate bone formation by inhibiting sympathetic activity through the central nervous system. PGE2 secreted by osteoblasts increases when bone density decreases as demonstrated in osteoporotic animal models. Ablation of sensory nerves erodes the skeletal integrity. Specifically, knockout of the EP4 gene in the sensory nerves or cyclooxygenase-2 (COX2) in the osteoblastic cells significantly reduces bone volume in adult mice. Sympathetic tone is increased in sensory denervation models, and propranolol, a ß2-adrenergic antagonist, rescues bone loss. Furthermore, injection of SW033291, a small molecule to increase PGE2 level locally, significantly boostes bone formation, whereas the effect is obstructed in EP4 knockout mice. Thus, we show that PGE2 mediates sensory nerve to control bone homeostasis and promote regeneration.


Assuntos
Osso e Ossos/metabolismo , Dinoprostona/metabolismo , Osteoporose/patologia , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Células Receptoras Sensoriais/metabolismo , Fibras Adrenérgicas/efeitos dos fármacos , Fibras Adrenérgicas/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Densidade Óssea/efeitos dos fármacos , Regeneração Óssea/efeitos dos fármacos , Osso e Ossos/citologia , Osso e Ossos/inervação , Osso e Ossos/patologia , Células Cultivadas , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Retroalimentação Fisiológica , Feminino , Humanos , Hidroxiprostaglandina Desidrogenases/antagonistas & inibidores , Hidroxiprostaglandina Desidrogenases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoporose/etiologia , Propranolol/farmacologia , Piridinas/farmacologia , Receptores de Prostaglandina E Subtipo EP4/genética , Células Receptoras Sensoriais/efeitos dos fármacos , Tiofenos/farmacologia
6.
FASEB J ; 33(4): 4780-4789, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30601680

RESUMO

Prostaglandin E2 (PGE2) is produced in the airway during allergic lung inflammation and both promotes and inhibits features of asthma pathology. These mixed effects relate to 4 E-prostanoid (EP) receptor subtypes (EP1, 2, 3 and 4) expressed at different levels on different resident and infiltrating airway cells. Although studies have asserted both EP2 and EP4 expression in human airway smooth muscle (HASM), a recent study asserted EP4 to be the functionally dominant EP subtype in HASM. Herein, we employ recently-developed subtype-selective ligands to investigate singular or combined EP2 and EP4 receptor activation in regulating HASM signaling and proliferation. The subtype specificity of ONO-AE1-259-01 (EP2 agonist) and ONO-AE1-329 (EP4 agonist) was first demonstrated in human embryonic kidney 293 cells stably expressing different EP receptor subtypes. EP receptor knockdown and subtype-selective antagonists demonstrated EP2 and EP4 receptor responsiveness in HASM cells to the specific ONO compounds, whereas PGE2 appeared to preferentially signal via the EP4 receptor. Both singular EP2 and EP4 receptor agonists inhibited HASM proliferation, and combined EP2 and EP4 receptor agonism exhibited positive cooperativity in both chronic Gs-mediated signaling and inhibiting HASM proliferation. These findings suggest both EP2 and EP4 are functionally important in HASM, and their combined targeting optimally inhibits airway smooth muscle proliferation.-Michael, J. V. Gavrila, A., Nayak, A. P., Pera, T., Liberato, J. R., Polischak, S. R., Shah, S. D., Deshpande, D. A., Penn, R. B. Cooperativity of E-prostanoid receptor subtypes in regulating signaling and growth inhibition in human airway smooth muscle.


Assuntos
Músculo Liso/metabolismo , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP3/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Cálcio/metabolismo , AMP Cíclico/metabolismo , Células HEK293 , Humanos , Immunoblotting , Microscopia Confocal , RNA Interferente Pequeno/genética , Receptores de Prostaglandina E Subtipo EP2/genética , Receptores de Prostaglandina E Subtipo EP3/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Transdução de Sinais/fisiologia
7.
J Allergy Clin Immunol ; 143(2): 631-643, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29935220

RESUMO

BACKGROUND: IL-23 is the key cytokine for generation of pathogenic IL-17-producing helper T (TH17) cells, which contribute critically to autoimmune diseases. However, how IL-23 generates pathogenic TH17 cells remains to be elucidated. OBJECTIVES: We sought to examine the involvement, molecular mechanisms, and clinical implications of prostaglandin (PG) E2-EP2/EP4 signaling in induction of IL-23-driven pathogenic TH17 cells. METHODS: The role of PGE2 in induction of pathogenic TH17 cells was investigated in mouse TH17 cells in culture in vitro and in an IL-23-induced psoriasis mouse model in vivo. Clinical relevance of the findings in mice was examined by using gene expression profiling of IL-23 and PGE2-EP2/EP4 signaling in psoriatic skin from patients. RESULTS: IL-23 induces Ptgs2, encoding COX2 in TH17 cells, and produces PGE2, which acts back on the PGE receptors EP2 and EP4 in these cells and enhances IL-23-induced expression of an IL-23 receptor subunit gene, Il23r, by activating signal transducer and activator of transcription (STAT) 3, cAMP-responsive element binding protein 1, and nuclear factor κ light chain enhancer of activated B cells (NF-κB) through cyclic AMP-protein kinase A signaling. This PGE2 signaling also induces expression of various inflammation-related genes, which possibly function in TH17 cell-mediated pathology. Combined deletion of EP2 and EP4 selectively in T cells suppressed accumulation of IL-17A+ and IL-17A+IFN-γ+ pathogenic Th17 cells and abolished skin inflammation in an IL-23-induced psoriasis mouse model. Analysis of human psoriatic skin biopsy specimens shows positive correlation between PGE2 signaling and the IL-23/TH17 pathway. CONCLUSIONS: T cell-intrinsic EP2/EP4 signaling is critical in IL-23-driven generation of pathogenic TH17 cells and consequent pathogenesis in the skin.


Assuntos
Inflamação/imunologia , Psoríase/imunologia , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Células Th17/imunologia , Animais , Células Cultivadas , AMP Cíclico/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Imiquimode , Interleucina-23/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Prostaglandina E Subtipo EP2/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Transdução de Sinais
8.
Nat Chem Biol ; 15(1): 18-26, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30510193

RESUMO

Prostaglandin E receptor EP4, a G-protein-coupled receptor, is involved in disorders such as cancer and autoimmune disease. Here, we report the crystal structure of human EP4 in complex with its antagonist ONO-AE3-208 and an inhibitory antibody at 3.2 Å resolution. The structure reveals that the extracellular surface is occluded by the extracellular loops and that the antagonist lies at the interface with the lipid bilayer, proximal to the highly conserved Arg316 residue in the seventh transmembrane domain. Functional and docking studies demonstrate that the natural agonist PGE2 binds in a similar manner. This structural information also provides insight into the ligand entry pathway from the membrane bilayer to the EP4 binding pocket. Furthermore, the structure reveals that the antibody allosterically affects the ligand binding of EP4. These results should facilitate the design of new therapeutic drugs targeting both orthosteric and allosteric sites in this receptor family.


Assuntos
Receptores de Prostaglandina E Subtipo EP4/química , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Regulação Alostérica , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Sítios de Ligação , Caprilatos/química , Caprilatos/metabolismo , Cristalografia por Raios X , Epoprostenol/análogos & derivados , Epoprostenol/química , Epoprostenol/metabolismo , Humanos , Ligantes , Bicamadas Lipídicas , Simulação de Acoplamento Molecular , Naftalenos/química , Naftalenos/metabolismo , Éteres Fenílicos/química , Éteres Fenílicos/metabolismo , Fenilbutiratos/química , Fenilbutiratos/metabolismo , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP4/genética , Spodoptera/genética
9.
Pharmacol Res Perspect ; 6(6): e00441, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30455960

RESUMO

The up-regulated expression of E-type prostanoid (EP) 4 receptors has been implicated in carcinogenesis; however, the expression of EP4 receptors has also been reported to be weaker in tumor tissues than in normal tissues. Indeed, EP4 receptors have been suggested to play a role in the maintenance of colorectal homeostasis. This study aimed to examine the underlying mechanisms/reasons for why inconsistent findings have been reported regarding EP4 receptor expression levels in homeostasis and carcinogenesis by focusing on cellular densities. Thus, the human colon cancer HCA-7 cells, which retain some functional features of normal epithelia, and luciferase reporter genes containing wild-type or mutated EP4 receptor promoters were used for elucidating the cellular density-dependent mechanisms about the regulation of EP4 receptor expression. In silico analysis was also utilized for confirming the relevance of the findings with respect to colon cancer development. We here demonstrated that the expression of EP4 receptors was up-regulated by c-Myc by binding to Sp-1 under low cellular density conditions, but was down-regulated under high cellular density conditions via the increase in the expression levels of HIF-1α protein, which may pull out c-Myc and Sp-1 from DNA-binding. The tightly regulated EP4 receptor expression mechanism may be a critical system for maintaining homeostasis in normal colorectal epithelial cells. Therefore, once the system is altered, possibly due to the transient overexpression of EP4 receptors, it may result in aberrant cellular proliferation and transformation to cancerous phenotypes. However, at the point, EP4 receptors themselves and their mediated homeostasis would be no longer required.


Assuntos
Neoplasias do Colo/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores de Prostaglandina E Subtipo EP4/genética , Carcinogênese/genética , Contagem de Células , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Biologia Computacional , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Fator de Transcrição Sp1/metabolismo , Regulação para Cima
10.
BMB Rep ; 51(10): 532-537, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30269738

RESUMO

Prostaglandin E2 (PGE2), a major product of cyclooxygenase-2 (COX-2), plays an important role in the carcinogenesis of many solid tumors, including colorectal cancer. Because PGE2 functions by signaling through PGE2 receptors (EPs), which regulate tumor cell growth, invasion, and migration, there has been a growing amount of interest in the therapeutic potential of targeting EPs. In the present study, we investigated the role of EP4 on the effectiveness of cordycepin in inhibiting the migration and invasion of HCT116 human colorectal carcinoma cells. Our data indicate that cordycepin suppressed lipopolysaccharide (LPS)-enhanced cell migration and invasion through the inactivation of matrix metalloproteinase (MMP)-9 as well as the down-regulation of COX-2 expression and PGE2 production. These events were shown to be associated with the inactivation of EP4 and activation of AMP-activated protein kinase (AMPK). Moreover, the EP4 antagonist AH23848 prevented LPS-induced MMP-9 expression and cell invasion in HCT116 cells. However, the AMPK inhibitor, compound C, as well as AMPK knockdown via siRNA, attenuated the cordycepin-induced inhibition of EP4 expression. Cordycepin treatment also reduced the activation of CREB. These findings indicate that cordycepin suppresses the migration and invasion of HCT116 cells through modulating EP4 expression and the AMPK-CREB signaling pathway. Therefore, cordycepin has the potential to serve as a potent anti-cancer agent in therapeutic strategies against colorectal cancer metastasis. [BMB Reports 2018; 51(10): 533-538].


Assuntos
Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Desoxiadenosinas/farmacologia , Regulação para Baixo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Adenilato Quinase/metabolismo , Neoplasias Colorretais/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Lipopolissacarídeos , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica , Receptores de Prostaglandina E Subtipo EP4/genética , Transdução de Sinais/efeitos dos fármacos
11.
Stroke ; 49(9): 2191-2199, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30354987

RESUMO

Background and Purpose- Many restorative therapies have been used to study brain repair after stroke. These therapeutic-induced changes have revealed important insights on brain repair and recovery mechanisms; however, the intrinsic changes that occur in spontaneously recovery after stroke is less clear. The goal of this study is to elucidate the intrinsic changes in spontaneous recovery after stroke, by directly investigating the transcriptome of primary motor cortex in mice that naturally recovered after stroke. Methods- Male C57BL/6J mice were subjected to transient middle cerebral artery occlusion. Functional recovery was evaluated using the horizontal rotating beam test. A novel in-depth lesion mapping analysis was used to evaluate infarct size and locations. Ipsilesional and contralesional primary motor cortices (iM1 and cM1) were processed for RNA-sequencing transcriptome analysis. Results- Cluster analysis of the stroke mice behavior performance revealed 2 distinct recovery groups: a spontaneously recovered and a nonrecovered group. Both groups showed similar lesion profile, despite their differential recovery outcome. RNA-sequencing transcriptome analysis revealed distinct biological pathways in the spontaneously recovered stroke mice, in both iM1 and cM1. Correlation analysis revealed that 38 genes in the iM1 were significantly correlated with improved recovery, whereas 74 genes were correlated in the cM1. In particular, ingenuity pathway analysis highlighted the involvement of cAMP signaling in the cM1, with selective reduction of Adora2a (adenosine receptor A2A), Drd2 (dopamine receptor D2), and Pde10a (phosphodiesterase 10A) expression in recovered mice. Interestingly, the expressions of these genes in cM1 were negatively correlated with behavioral recovery. Conclusions- Our RNA-sequencing data revealed a panel of recovery-related genes in the motor cortex of spontaneously recovered stroke mice and highlighted the involvement of contralesional cortex in spontaneous recovery, particularly Adora2a, Drd2, and Pde10a-mediated cAMP signaling pathway. Developing drugs targeting these candidates after stroke may provide beneficial recovery outcome.


Assuntos
Infarto da Artéria Cerebral Média/genética , Córtex Motor/metabolismo , RNA Mensageiro/metabolismo , Recuperação de Função Fisiológica/genética , Animais , Análise por Conglomerados , AMP Cíclico/metabolismo , Perfilação da Expressão Gênica , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Imagem por Ressonância Magnética , Camundongos , Córtex Motor/diagnóstico por imagem , Córtex Motor/patologia , Córtex Motor/fisiopatologia , Diester Fosfórico Hidrolases/genética , Receptor A2A de Adenosina/genética , Receptores de Dopamina D2/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Remissão Espontânea , Análise de Sequência de RNA , Transdução de Sinais , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia
12.
Mol Med Rep ; 18(6): 5141-5150, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30320390

RESUMO

Prostaglandin E2 has exhibited pleiotropic effects in the regulation of glomerulosclerosis progression through its four receptors. The current study aimed to evaluate the effect of prostaglandin receptor EP4 on mesangial cell proliferation. In vivo, 5/6 nephrectomy was introduced into EP4+/­ and wild­type (WT) mice. Clinical parameters were monitored post­surgery. At 8 weeks post­surgery, glomerular fibrosis­associated indicators were measured by immunohistochemical staining and trichrome staining. In vitro, mesangial cells in different groups (transfected with green fluorescent protein, AD­EF4 or AD­CRE) were exposed to transforming growth factor (TGF)­ß1 for 24 h to detect the level of downstream signaling. Corresponding signaling inhibitors were also used to validate the signaling effects. Following surgery, EP4+/­ mice presented a higher survival rate and normal urine volume compared with the WT group, and serum creatinine level and 24 h urine protein were lower in the EP4+/­ mice. Furthermore, associated profibrotic indicators were identified to have decreased at 8 weeks post­surgery along with less tubule­interstitial fibrosis. In vivo, the inhibition of extracellular signal­regulated kinase and P38 phosphorylation alleviated the accumulation of mesangial matrix, and these signals were enhanced when EP4 was overexpressed. EP4 enhancement aggravated imbalanced mesangial cell proliferation stimulated by TGF­ß1 and GS of mice treated with 5/6 nephrectomy through the Smad and mitogen­activated protein kinase pathways.


Assuntos
Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/metabolismo , Células Mesangiais/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Receptores de Prostaglandina E Subtipo EP4/deficiência , Transdução de Sinais , Proteínas Smad/metabolismo , Animais , Biomarcadores , Células Cultivadas , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Expressão Gênica , Técnicas de Silenciamento de Genes , Glomerulosclerose Segmentar e Focal/patologia , Células Mesangiais/patologia , Camundongos , Camundongos Knockout , Nefrotomia , Receptores de Prostaglandina E Subtipo EP4/genética , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
13.
Cancer Med ; 7(10): 5057-5065, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30191681

RESUMO

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10-04 ) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10-09 ). On chromosome 5p13 we found cis-eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10-11 ). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10-47 ). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10-09 ). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms.


Assuntos
Aciltransferases/genética , Antígenos de Neoplasias/genética , Perfilação da Expressão Gênica/métodos , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Neoplasias Gástricas/genética , Estudos de Casos e Controles , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 8/genética , Feminino , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
14.
PLoS One ; 13(9): e0203211, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30192865

RESUMO

BACKGROUND: Sphingosine kinase phosphorylates sphingosine to generate sphingosine 1 phosphate (S1P) following stimulation of the five plasma membrane G-protein-coupled receptors. The objective of this study is to clarify the role of S1P and its receptors (S1PRs), especially S1PR3 in airway epithelial cells. METHODS: The effects of S1P on asthma-related genes expression were examined with the human bronchial epithelial cells BEAS-2B and Calu-3 using a transcriptome analysis and siRNA of S1PRs. To clarify the role of CCL20 in the airway inflammation, BALB/c mice were immunized with ovalbumin (OVA) and subsequently challenged with an OVA-containing aerosol to induce asthma with or without intraperitoneal administration of anti-CCL20. Finally, the anti-inflammatory effect of VPC 23019, S1PR1/3 antagonist, in the OVA-induced asthma was examined. RESULTS: S1P induced the expression of some asthma-related genes, such as ADRB2, PTGER4, and CCL20, in the bronchial epithelial cells. The knock-down of SIPR3 suppressed the expression of S1P-inducing CCL20. Anti-CCL20 antibody significantly attenuated the eosinophil numbers in the bronchoalveolar lavage fluid (P<0.01). Upon OVA challenge, VPC23019 exhibited substantially attenuated eosinophilic inflammation. CONCLUSIONS: S1P/S1PR3 pathways have a role in release of proinflammatory cytokines from bronchial epithelial cells. Our results suggest that S1P/S1PR3 may be a possible candidate for the treatment of bronchial asthma.


Assuntos
Brônquios/imunologia , Brônquios/metabolismo , Quimiocina CCL20/metabolismo , Lisofosfolipídeos/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/análogos & derivados , Animais , Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Asma/genética , Asma/metabolismo , Brônquios/patologia , Linhagem Celular , Modelos Animais de Doenças , Eosinofilia/tratamento farmacológico , Eosinofilia/patologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Fosfosserina/análogos & derivados , Fosfosserina/farmacologia , Receptores Adrenérgicos beta 2/genética , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Receptores de Lisoesfingolipídeo/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Esfingosina/metabolismo
15.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1863(10): 1297-1304, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30053598

RESUMO

Prostaglandin E2 (PGE2) is responsible for inflammatory symptoms. However, PGE2 also suppresses pro-inflammatory cytokine production. There are at least 4 subtypes of PGE2 receptors, EP1-EP4, but it is unclear which of these specifically control cytokine production. The aim of this study was to determine which of the different receptors, EP1R-EP4R modulate production of tumor necrosis factor-α (TNF-α) in human monocytic cells. Human blood, or the human monocytic cell line THP-1 were stimulated with LPS. The actions of PGE2, alongside selective agonists of EP1-EP4 receptors, were assessed on LPS-induced TNF-α, IL-1ß and IL-10 release. The expression profiles of EP2R and EP4R in monocytes and THP-1 cells were characterised by RT-qPCR. In addition, the production of cytokines was evaluated following knockdown of the receptors using siRNA and over-expression of the receptors by transfection with constructs. PGE2 and also EP2 and EP4 agonists (but not EP1 or EP3 agonists) suppressed TNF-α production in blood and THP-1 cells. LPS also up regulated expression of EP2R and EP4R but not EP1 or EP3. siRNA for either EP2R or EP4R reversed the suppressive actions of PGE2 on cytokine production and overexpression of EP2R and EP4R enhanced the suppressive actions of PGE2. This indicates that PGE2 suppression of TNF-α by human monocytic cells occurs via EP2R and EP4R expression. However EP4Rs also control their own expression and that of EP2 whereas the EP2R does not affect EP4R expression. This implies that EP4 receptors have an important master role in controlling inflammatory responses.


Assuntos
Dinoprostona/efeitos adversos , Monócitos/citologia , Receptores de Prostaglandina E Subtipo EP2/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Fator de Necrose Tumoral alfa/metabolismo , Dinoprostona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/efeitos adversos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Receptores de Prostaglandina E Subtipo EP2/agonistas , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP4/agonistas , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Células THP-1
16.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1863(9): 1029-1040, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29890224

RESUMO

Prostaglandin E receptor subtype 4 (EP4) knockout mice develops spontaneous hypercholesterolemia but the detailed mechanisms by which EP4 affects cholesterol homeostasis remains unexplored. We sought to determine the cause of hypercholesterolemia in EP4 knockout mice, focusing on the role of EP4 in regulating the synthesis and elimination of cholesterol. Deficiency of EP4 significantly decreased total bile acid levels in the liver by 26.2% and the fecal bile acid content by 27.6% as compared to wild type littermates, indicating that the absence of EP4 decreased hepatic bile acid synthesis and their subsequent excretion in stools. EP4 deficiency negatively regulate bile acid synthesis through repression of phosphorylated extracellular signal-regulated kinase 1/2 (ERK)-mediated cholesterol 7α-hydroxylase (CYP7A1) expression and that the hypercholesterolemia in EP4 knockout mice is due to a defect in cholesterol conversion into bile acids. Deficiency of EP4 also increased de novo cholesterol synthesis and altered cholesterol fluxes in and out of the liver. Treating high fat diet-challenged mice with the pharmacological EP4 agonist, CAY10580 (200 µg/kg body weight/day i.p) for three weeks effectively prevented diet-induced hypercholesterolemia, enhanced endogenous bile acid synthesis and their fecal excretion. In summary, EP4 plays a critical role in maintaining cholesterol homeostasis by regulating the synthesis and elimination of bile acids. Activation of EP4 serves as an effective novel strategy to promote cholesterol disposal in the forms of bile acids in order to lower plasma cholesterol levels.


Assuntos
Anticolesterolemiantes/farmacologia , Ácidos e Sais Biliares/deficiência , Colesterol/metabolismo , Dinoprostona/análogos & derivados , Hipercolesterolemia/genética , Pirrolidinonas/farmacologia , Receptores de Prostaglandina E Subtipo EP4/genética , Animais , Ácidos e Sais Biliares/biossíntese , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Dieta Hiperlipídica/efeitos adversos , Dinoprostona/farmacologia , Fezes/química , Regulação da Expressão Gênica , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Receptores de Prostaglandina E Subtipo EP4/deficiência , Transdução de Sinais
17.
Front Immunol ; 9: 501, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29593738

RESUMO

Evidence is accumulating that group 2 innate lymphoid cells (ILC2) play an important role in allergic airway inflammation by producing a large amount of type 2 cytokines. But it remains poorly understood how its activities are properly controlled in vivo. Here, we demonstrated that prostaglandin E2 (PGE2) had a profound inhibitory effect on IL-33-induced ILC2 expansion and IL-5 and IL-13 production in vitro. This effect was mimicked by PGE1-alcohol but attenuated by ONO-AE3-208, indicating a selective action through the E-prostanoid 4 (EP4) receptor. In the IL-33-induced asthma model, coadministration of PGE2 or PGE1-alcohol resulted in diminished IL-5 and IL-13 production, reduced eosinophilia and alleviated lung pathology. In contrast, EP4-deficient mice displayed an exacerbated inflammatory response in another ILC2-mediated asthma model induced by Alternaria extract. Mechanistic studies demonstrated that the PGE2-mediated inhibition of ILC2 was dependent on cyclic adenosine monophosphate (cAMP) production. Further downstream, PGE2-EP4-cAMP signaling led to suppression of GATA3 and ST2 expression, which is known to be critical for ILC2 activation. These findings reveal a novel function of PGE2 as a negative regulator of ILC2 activation and highlight an endogenous counter-regulatory mechanism for the control of innate allergic inflammatory responses.


Assuntos
Asma/imunologia , Dinoprostona/metabolismo , Linfócitos/imunologia , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Hipersensibilidade Respiratória/imunologia , Animais , AMP Cíclico/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Humanos , Imunidade Inata , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Prostaglandina E Subtipo EP4/genética , Transdução de Sinais , Células Th2/imunologia
18.
J Mol Cell Cardiol ; 118: 1-12, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29522761

RESUMO

BACKGROUND: Prostaglandin E2 (PGE2) signals through 4 separate G-protein coupled receptor sub-types to elicit a variety of physiologic and pathophysiological effects. We recently reported that PGE2 via its EP3 receptor could reduce cardiac contractility of isolated myocytes and the working heart preparation. We thus hypothesized that there is an imbalance in the EP3/EP4 ratio towards EP3 in the failing heart and that overexpression of EP4 in a mouse model of heart failure would improve cardiac function. METHODS AND RESULTS: Our hypothesis was tested in a mouse model of myocardial infarction (MI) with the use of AAV9-EP4 driven by the myosin heavy chain promoter to overexpress EP4 in the cardiac myocytes. Echocardiography was performed to assess cardiac function. We found that overexpression of EP4 improved shortening fraction (p = 0.0025), ejection fraction (p = 0.0003), and reduced left ventricular dimension at systole (p = 0.0013). Overexpression of EP4 also significantly reduced indices of cardiac hypertrophy and interstitial collagen fraction. Animals treated with AAV9-EP4 also had a significant decrease in TNFα mRNA expression and in the number of macrophages and T cells migrated post MI coupled with a reduction in the expression of iNOS. CONCLUSION: Overexpression of EP4 improves cardiac function post MI. This may be mediated through reductions in adverse cardiac remodeling or via inhibition of cytokine/chemokine production.


Assuntos
Coração/fisiopatologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Cardiomegalia/genética , Cardiomegalia/patologia , Movimento Celular , Polaridade Celular , Colágeno/metabolismo , Citocinas/metabolismo , Dependovirus/metabolismo , Ventrículos do Coração/metabolismo , Macrófagos/patologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/diagnóstico por imagem , Miócitos Cardíacos/metabolismo , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Prostaglandina E Subtipo EP4/genética , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
Int J Mol Sci ; 19(4)2018 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-29596308

RESUMO

G-protein-coupled receptors (GPCRs, also called seven-transmembrane or heptahelical receptors) are a superfamily of cell surface receptor proteins that bind to many extracellular ligands and transmit signals to an intracellular guanine nucleotide-binding protein (G-protein). When a ligand binds, the receptor activates the attached G-protein by causing the exchange of Guanosine-5'-triphosphate (GTP) for guanosine diphosphate (GDP). They play a major role in many physiological functions, as well as in the pathology of many diseases, including cancer progression and metastasis. Only a few GPCR members have been exploited as targets for developing drugs with therapeutic benefit in cancer. Present review briefly summarizes the signaling pathways utilized by the EP (prostaglandin E receptor) family of GPCR, their physiological and pathological roles in carcinogenesis, with special emphasis on the roles of EP4 in breast cancer progression. We make a case for EP4 as a promising newer therapeutic target for treating breast cancer. We show that an aberrant over-expression of cyclooxygenase (COX)-2, which is an inflammation-associated enzyme, occurring in 40-50% of breast cancer patients leads to tumor progression and metastasis due to multiple cellular events resulting from an increased prostaglandin (PG) E2 production in the tumor milieu. They include inactivation of host anti-tumor immune cells, such as Natural Killer (NK) and T cells, increased immuno-suppressor function of tumor-associated macrophages, promotion of tumor cell migration, invasiveness and tumor-associated angiogenesis, due to upregulation of multiple angiogenic factors including Vascular Endothelial Growth Factor (VEGF)-A, increased lymphangiogenesis (due to upregulation of VEGF-C/D), and a stimulation of stem-like cell (SLC) phenotype in cancer cells. All of these events were primarily mediated by activation of the Prostaglandin (PG) E receptor EP4 on tumor or host cells. We show that selective EP4 antagonists (EP4A) could mitigate all of these events tested with cells in vitro as well as in vivo in syngeneic COX-2 expressing mammary cancer bearing mice or immune-deficient mice bearing COX-2 over-expressing human breast cancer xenografts. We suggest that EP4A can avoid thrombo-embolic side effects of long term use of COX-2 inhibitors by sparing cardio-protective roles of PGI2 via IP receptor activation or PGE2 via EP3 receptor activation. Furthermore, we identified two COX-2/EP4 induced oncogenic and SLC-stimulating microRNAs-miR526b and miR655, one of which (miR655) appears to be a potential blood biomarker in breast cancer patients for monitoring SLC-ablative therapies, such as with EP4A. We suggest that EP4A will likely produce the highest benefit in aggressive breast cancers, such as COX-2 expressing triple-negative breast cancers, when combined with other newer agents, such as inhibitors of programmed cell death (PD)-1 or PD-L1.


Assuntos
Proteínas de Neoplasias , Receptores de Prostaglandina E Subtipo EP4 , Neoplasias de Mama Triplo Negativas , Dinoprostona/genética , Dinoprostona/metabolismo , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP4/genética , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
20.
Arterioscler Thromb Vasc Biol ; 38(5): 1115-1124, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29599139

RESUMO

OBJECTIVE: Deletion of mPGES-1 (microsomal prostaglandin E synthase-1)-an anti-inflammatory target alternative to COX (cyclooxygenase)-2-attenuates injury-induced neointima formation in mice. This is attributable to the augmented levels of PGI2 (prostacyclin)-a known restraint of the vascular response to injury, acting via IP (I prostanoid receptor). To examine the role of mPGES-1-derived PGE2 (prostaglandin E2) in vascular remodeling without the IP. APPROACH AND RESULTS: Mice deficient in both IP and mPGES-1 (DKO [double knockout] and littermate controls [IP KO (knockout)]) were subjected to angioplasty wire injury. Compared with the deletion of IP alone, coincident deletion of IP and mPGES-1 increased neointima formation, without affecting media area. Early pathological changes include impaired reendothelialization and increased leukocyte invasion in neointima. Endothelial cells (ECs), but not vascular smooth muscle cells, isolated from DKOs exhibited impaired cell proliferation. Activation of EP (E prostanoid receptor) 4 (and EP2, to a lesser extent), but not of EP1 or EP3, promoted EC proliferation. EP4 antagonism inhibited proliferation of mPGES-1-competent ECs, but not of mPGES-1-deficient ECs, which showed suppressed PGE2 production. EP4 activation inhibited leukocyte adhesion to ECs in vitro, promoted reendothelialization, and limited neointima formation post-injury in the mouse. Endothelium-restricted deletion of EP4 in mice suppressed reendothelialization, increased neointimal leukocytes, and exacerbated neointimal formation. CONCLUSIONS: Removal of the IP receptors unmasks a protective role of mPGES-1-derived PGE2 in limiting injury-induced vascular hyperplasia. EP4, in the endothelial compartment, is essential to promote reendothelialization and restrain neointimal formation after injury. Activating EP4 bears therapeutic potential to prevent restenosis after percutaneous coronary intervention.


Assuntos
Proliferação de Células , Dinoprostona/metabolismo , Células Endoteliais/enzimologia , Artéria Femoral/enzimologia , Prostaglandina-E Sintases/metabolismo , Receptores de Epoprostenol/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Lesões do Sistema Vascular/enzimologia , Animais , Adesão Celular , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/patologia , Feminino , Artéria Femoral/lesões , Artéria Femoral/patologia , Humanos , Leucócitos/metabolismo , Leucócitos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso/enzimologia , Músculo Liso/patologia , Neointima , Prostaglandina-E Sintases/deficiência , Prostaglandina-E Sintases/genética , Reepitelização , Receptores de Epoprostenol/deficiência , Receptores de Epoprostenol/genética , Receptores de Prostaglandina E Subtipo EP4/deficiência , Receptores de Prostaglandina E Subtipo EP4/genética , Transdução de Sinais , Lesões do Sistema Vascular/genética , Lesões do Sistema Vascular/patologia
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