scholarly journals Prostaglandin E 2 induced cardiac hypertrophy through EP2 receptor‐dependent activation of β‐catenin in 5/6 nephrectomy rats

2021 ◽  
Author(s):  
Yaqiong Wang ◽  
Ting Zhang ◽  
Xuesen Cao ◽  
Jianzhou Zou ◽  
Xiaoqiang Ding ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Prostaglandin E ◽  
Ep2 Receptor

Knockout of the Prostaglandin E2 Receptor Subtype 3 Promotes Eccentric Cardiac Hypertrophy and Fibrosis in Mice

2016 ◽  
Vol 22 (1) ◽  
pp. 71-82 ◽  
Author(s):  
Shuang Liu ◽  
Yawei Ji ◽  
Jian Yao ◽  
Xiaodan Zhao ◽  
Hu Xu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Messenger Rna ◽  
Cardiac Fibrosis ◽  
Glycogen Synthase ◽  
Mrna Level ◽  
Matrix Metalloproteinase 2 ◽  
Prostaglandin E ◽  
Receptor Subtype ◽  
The Impact ◽  
Subtype 3

Background: Prostaglandin E2 receptor subtype 3 (EP3), a Gi protein-coupled receptor activated by prostaglandin E2, plays a particular role in cardioprotection. This study aimed to investigate the impact of EP3 deletion on cardiac remodeling and further elucidate the related involvement of possible signaling pathways. Methods and Results: The animals used were EP3 receptor knockout (EP3KO) mice and wild-type (WT) litter mate controls at 16-18 weeks old. The high-resolution echocardiography and weight index indicated that eccentric cardiac hypertrophy might occur in EP3KO mice, which were having worse cardiac function than WT litter mates. Isolated adult myocytes from EP3KO hearts showed spontaneous lengthening. Cardiac fibrosis was observed in EP3KO mice through Masson trichrome staining. The elevated messenger RNA (mRNA) level in matrix genes and the reduced mRNA, protein, and activity levels of matrix metalloproteinase 2 (MMP-2) indicated an increased synthesis and suppressed degradation of matrix collagen in EP3KO mice. The phosphorylation level of extracellular signal-regulated kinase (ERK) 1/2 protein was reduced in the cardiac tissue of EP3KO mice, accompanied by no significant change in the protein level of total ERK1/2, total p38, phospho-p38, glycogen synthase kinase-3β (GSK3β), phospho-GSK3β, and calcineurin (CaN) as well as CaN activity. Conclusion: EP3 knockout in cardiac tissues could induce eccentric cardiac hypertrophy and cardiac fibrosis at 16-18 weeks old. These effects of EP3 knockout might be regulated through inactivating MAPK/ERK pathway and affecting the MMP-2 expression. Overall, PGE2-EP3 is necessary to maintain the normal growth and development of the heart.

scholarly journals The protective effects of 18β-glycyrrhetinic acid against inflammation microenvironment in gastric tumorigenesis targeting PGE2-EP2 receptor-mediated arachidonic acid pathway

2018 ◽  
Vol 16 ◽  
pp. 205873921876299 ◽  
Author(s):  
Donghui Cao ◽  
Jing Jiang ◽  
Dan Zhao ◽  
Menghui Wu ◽  
Houjun Zhang ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Glycyrrhetinic Acid ◽  
Prostaglandin E ◽  
Protective Effects ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Acid Pathway ◽  
Ep2 Receptor ◽  
Arachidonic Acid Pathway

Accumulating epidemiological and clinical evidence shows that inflammation is an important risk factor for gastrointestinal diseases. Glycyrrhiza glabra, a traditional Chinese medicine, has been shown to safely suppress gastric cancer; however, the anti-inflammatory mechanisms in gastric tumorigenesis have been poorly investigated. Therefore, this study is committed to demonstrate the in vivo anti-inflammatory effect of 18β-glycyrrhetinic acid (GRA), the main active component of G. glabra. The lymphocytes and macrophages were heavily infiltrated in the transgenic mice that highly expressed cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1; however, a significant reduction was observed after treatment with GRA. In addition, GRA downregulated the protein levels of COX-2, GαS, EP2, and β-catenin, which were involved in the arachidonic acid pathway. In conclusion, our study showed the potential protective effects of GRA against inflammatory environment that might be involved in gastric tumorigenesis in vivo through the PGE2-EP2 receptor-mediated arachidonic acid pathway.

scholarly journals An EP2 Agonist Facilitates NMDA-Induced Outward Currents and Inhibits Dendritic Beading through Activation of BK Channels in Mouse Cortical Neurons

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Yoshinori Hayashi ◽  
Saori Morinaga ◽  
Xia Liu ◽  
Jing Zhang ◽  
Zhou Wu ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Cortical Neurons ◽  
Receptor Agonist ◽  
Bk Channels ◽  
Bk Channel ◽  
Prostaglandin E ◽  
Receptor Subtypes ◽  
Prostanoid Receptor ◽  
Outward Currents ◽  
Ep2 Receptor

Prostaglandin E2(PGE2), a major metabolite of arachidonic acid produced by cyclooxygenase pathways, exerts its bioactive responses by activating four E-prostanoid receptor subtypes, EP1, EP2, EP3, and EP4. PGE2enables modulatingN-methyl-D-aspartate (NMDA) receptor-mediated responses. However, the effect of E-prostanoid receptor agonists on large-conductance Ca2+-activated K+(BK) channels, which are functionally coupled with NMDA receptors, remains unclear. Here, we showed that EP2 receptor-mediated signaling pathways increased NMDA-induced outward currents (INMDA-OUT), which are associated with the BK channel activation. Patch-clamp recordings from the acutely dissociated mouse cortical neurons revealed that an EP2 receptor agonist activatedINMDA-OUT, whereas an EP3 receptor agonist reduced it. Agonists of EP1 or EP4 receptors showed no significant effects onINMDA-OUT. A direct perfusion of 3,5′-cyclic adenosine monophosphate (cAMP) through the patch pipette facilitatedINMDA-OUT, which was abolished by the presence of protein kinase A (PKA) inhibitor. Furthermore, facilitation ofINMDA-OUTcaused by an EP2 receptor agonist was significantly suppressed by PKA inhibitor. Finally, the activation of BK channels through EP2 receptors facilitated the recovery phase of NMDA-induced dendritic beading in the primary cultured cortical neurons. These results suggest that a direct activation of BK channels by EP2 receptor-mediated signaling pathways plays neuroprotective roles in cortical neurons.

scholarly journals 15-Keto-PGE2 acts as a biased/partial agonist to terminate PGE2-evoked signaling

2020 ◽  
Vol 295 (38) ◽  
pp. 13338-13352 ◽  
Author(s):  
Suzu Endo ◽  
Akiko Suganami ◽  
Keijo Fukushima ◽  
Kanaho Senoo ◽  
Yumi Araki ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Partial Agonist ◽  
Cancer Development ◽  
Prostaglandin E ◽  
Prostanoid Receptors ◽  
Ep4 Receptor ◽  
Inactive Metabolite ◽  
Ep2 Receptor ◽  
Additional Role ◽  
Shed Light

Prostaglandin E2 (PGE2) is well-known as an endogenous proinflammatory prostanoid synthesized from arachidonic acid by the activation of cyclooxygenase-2. E type prostanoid (EP) receptors are cognates for PGE2 that have four main subtypes: EP1 to EP4. Of these, the EP2 and EP4 prostanoid receptors have been shown to couple to Gαs-protein and can activate adenylyl cyclase to form cAMP. Studies suggest that EP4 receptors are involved in colorectal homeostasis and cancer development, but further work is needed to identify the roles of EP2 receptors in these functions. After sufficient inflammation has been evoked by PGE2, it is metabolized to 15-keto-PGE2. Thus, 15-keto-PGE2 has long been considered an inactive metabolite of PGE2. However, it may have an additional role as a biased and/or partial agonist capable of taking over the actions of PGE2 to gradually terminate reactions. Here, using cell-based experiments and in silico simulations, we show that PGE2-activated EP4 receptor–mediated signaling may evoke the primary initiating reaction of the cells, which would take over the 15-keto-PGE2–activated EP2 receptor–mediated signaling after PGE2 is metabolized to 15-keto-PGE2. The present results shed light on new aspects of 15-keto-PGE2, which may have important roles in passing on activities to EP2 receptors from PGE2-stimulated EP4 receptors as a “switched agonist.” This novel mechanism may be significant for gradually terminating PGE2-evoked inflammation and/or maintaining homeostasis of colorectal tissues/cells functions.

scholarly journals Increased dietary NaCl induces renal medullary PGE2 production and natriuresis via the EP2 receptor

2008 ◽  
Vol 295 (3) ◽  
pp. F818-F825 ◽  
Author(s):  
Jian Chen ◽  
Min Zhao ◽  
Wenjuan He ◽  
Ginger L. Milne ◽  
Jocelyn R. H. Howard ◽  
...  
Keyword(s):  
Sodium Excretion ◽  
Urine Volume ◽  
High Salt ◽  
Negative Ion ◽  
Prostaglandin E ◽  
Ionization Mass ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Ep2 Receptor

A high-NaCl diet induces renal medullary cyclooxygenase (COX)2 expression, and selective intramedullary infusion of a COX2 inhibitor increases blood pressure in rats on a high-salt diet. The present study characterized the specific prostanoid contributing to the antihypertensive effect of COX2. C57BL/6J mice placed on a high-NaCl diet exhibited increased medullary COX2 and microsomal prostaglandin E synthase1 (mPGES1) expression as determined by immunoblot and real-time PCR. Cytosolic prostaglandin E synthase and prostacyclin synthase were not induced by the high-salt diet. Immunofluorescence showed mPGES1 in collecting ducts and interstitial cells. High salt increased renal medullary PGE2 as determined by gas chromatography/negative ion chemical ionization mass spectrometry. The effect of direct intramedullary PGE2 infusion was examined in anesthetized uninephrectomized mice. Intramedullary PGE2 infusion (10 ng/h) increased urine volume (from 3.3 ± 0.6 to 9.5 ± 1.6 μl/min) and urine sodium excretion (0.11 ± 0.02 to 0.32 ± 0.05 μeq/min). To determine which E-prostanoid (EP) receptor(s) mediated PGE2- dependent natriuresis, EP-selective prostanoids were infused. The EP2 agonist butaprost produced natriuresis (from 0.06 ± 0.02 to 0.32 ± 0.05 μeq/min). The natriuretic effect of intramedullary PGE2 or butaprost was abolished in EP2-deficient mice, which exhibit NaCl-dependent hypertension. In conclusion, a high-salt diet increases renal medullary COX2 and mPGES1 expression, and increases renal medullary PGE2 synthesis. Renal medullary PGE2 promotes renal sodium excretion via the EP2 receptor, thereby maintaining normotension in the setting of high salt intake.

Luminal prostaglandin E receptors regulate salt and water transport in rabbit cortical collecting duct

1995 ◽  
Vol 269 (2) ◽  
pp. F257-F265 ◽  
Author(s):  
Y. Sakairi ◽  
H. R. Jacobson ◽  
T. D. Noland ◽  
M. D. Breyer
Keyword(s):  
Collecting Duct ◽  
Prostaglandin E ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Cortical Collecting Duct ◽  
Dietary Salt ◽  
Ep4 Receptor ◽  
Osmotic Water ◽  
Dietary Salt Restriction ◽  
Ep2 Receptor

Prostaglandin E2 (PGE2) is the major renal cyclooxygenase metabolite of arachidonic acid. Urinary excretion of PGE2 is increased by dietary salt restriction, as well in cirrhosis and congestive heart failure. To determine whether urinary PGE2 affects transport along the nephron, the actions of luminal PGE2 were studied in the isolated perfused rabbit cortical collecting duct (CCD). Luminal PGE2 transiently hyperpolarized transepithelial voltage (Vt) in a dose-dependent manner (half-maximal effect approximately 10(-8) M) in contrast to a sustained depolarization of Vt produced by basolateral PGE2. Luminal PGE2 (0.1 microM) also significantly stimulated osmotic water permeability in the CCD. In CCDs cultured on semipermeable supports, apical PGE2 stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production, suggesting the effects of luminal PGE2 are mediated by adenylyl cyclase-stimulating EP2 or EP4 receptors. Sulprostone, a PGE2 analogue selective for EP1 and EP3 receptors, affected Vt only when applied from the basolateral but not the luminal surface. Luminal application of the EP2 receptor agonist butaprost was also without effect. These results suggest that luminal PGE2 affects Vt via a butaprost-insensitive EP4 receptor. The Vt effect of luminal PGE2 was not blocked by pertussis toxin, also arguing against an EP3-mediated Gi-coupled effect. Finally, 1 microM luminal PGE2 only slightly increased CCD intracellular calcium concentration ([Ca2+]i), in contrast to the marked increase in [Ca2+]i produced by basolateral PGE2 (0.1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals An investigation of the effect of the prostaglandin EP2 receptor agonist, butaprost, on the human isolated myometrium from pregnant and non-pregnant women

2002 ◽  
Vol 172 (2) ◽  
pp. 263-269 ◽  
Author(s):  
N Duckworth ◽  
K Marshall ◽  
JK Clayton
Keyword(s):  
Receptor Agonist ◽  
Bolus Dose ◽  
Human Myometrium ◽  
Prostaglandin E ◽  
Intracellular Camp ◽  
Thromboxane Receptor ◽  
Dependent Inhibition ◽  
Set Up ◽  
Ep2 Receptor ◽  
Camp Levels

The aim of this study was to compare the effect of two known spasmogens, oxytocin and the stable thromboxane receptor mimetic, U46619, on human myometrium treated with the prostaglandin E receptor (EP2) agonist, butaprost (selective for the EP2 receptor). Strips of myometrium from pregnant and non-pregnant donors were set up in a superfusion apparatus. Butaprost was administered as a bolus dose and via infusion. During the infusion of 10(-6) M butaprost, spasmogens were administered as bolus doses. Butaprost caused dose-related inhibition of myometrial activity when administered as a bolus dose (3-100 nmol) and concentration-dependent inhibition during infusion studies (10(-8)-10(-5 )M). Butaprost (10(-6 )M) attenuated the response to U46619 (0.l-10 nmol) in pregnant myometrium, but this difference was not statistically significant. Responses of pregnant myometrium to oxytocin (0.01-0.1 nmol) were significantly attenuated (P<0.05) in the presence of butaprost (10(-6)M). Butaprost physiologically antagonised the oxytocin response, possibly by increasing intracellular cAMP levels. This antagonism was much more marked than that seen with butaprost and U46619. It is unclear why these two types of antagonism differ and this effect is currently being investigated further using other prostanoid and non-prostanoid agents.

scholarly journals Stimulation of tube formation mediated through the prostaglandin EP2 receptor in rat luteal endothelial cells

2011 ◽  
Vol 209 (1) ◽  
pp. 33-43 ◽  
Author(s):  
Toshihiro Sakurai ◽  
Kenta Suzuki ◽  
Mikihiro Yoshie ◽  
Keisuke Hashimoto ◽  
Eiichi Tachikawa ◽  
...  
Keyword(s):  
Tube Formation ◽  
Prostaglandin E ◽  
Cox Inhibitors ◽  
Extracellular Signal ◽  
Cox Inhibitor ◽  
Enhanced Tube ◽  
Percoll Density Gradient ◽  
Pre Treatment ◽  
Ep2 Receptor

To explore the role of prostaglandin E2 (PGE2) in angiogenesis in the developing corpus luteum, luteal microvascular endothelial-like cells (luteal ECs) were prepared from highly luteinizing ovaries of rats using the percoll density gradient method. The cells abundantly expressed the mRNAs of the endothelial markers CD31 (PECAM-1) and responded to the vascular endothelial growth factor (VEGF) to form in vitro tube structures on Matrigel. Cyclooxygenase (COX) inhibitors significantly suppressed tube formation in luteal ECs, whereas PGE2 counteracted the COX inhibitor-induced blockage. PGE2-induced tube formation was blocked by a cyclic AMP-dependent protein kinase A (PKA) inhibitor, H89. The antagonist against the PGE receptor type 2 (EP2 receptor), AH6809, completely inhibited PGE2-induced tube formation and partly suppressed the VEGF-induced tube formation but did not attenuate PGE2-induced phosphorylation of both AKT kinase and extracellular signal-regulated kinase 1/2. VEGF significantly enhanced the expression of COX-2 mRNAs detected by real-time RT-PCR and PGE2 secretion into the media measured by ELISA in luteal ECs. In turn, PGE2 stimulated VEGF expression. In vitro co-culture of luteal ECs with steroidogenic luteal cells (SLCs) promoted tube formation. Pre-treatment of SLCs with VEGF further enhanced tube formation of ECs, and this effect was blocked by the COX-2 inhibitor. This stimulatory effect was inhibited by treatment with AH6809. These data indicate that PGE2 exerts a direct stimulatory effect on tube formation mainly via the EP2 receptor/PKA signaling in luteal ECs. Our results suggest the possibility that the endogenous PGE2 that is produced from luteinizing follicular cells as well as ECs may stimulate luteal angiogenesis.

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