Inhibition of prostaglandin E2 signaling through the EP1 receptor does not affect prostacyclin production in human endothelial cells

Kaneshiro, Tatsuya; Okumura, Masae; Maalouf, Samer; Uflacker, Andre; Maruyama, Takayuki; Kawamori, Toshihiko

doi:10.1016/j.prostaglandins.2009.07.003

Cited by 9 publications

(7 citation statements)

References 20 publications

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“…Our data indicate that the PGE 2 /EP 1 axis modulates the prothrombotic state up-regulating TF expression and activity, in agreement with the findings of Kaneshiro et al (43). These authors, using a different experimental model, showed that inhibitors of EP 1 receptor decrease TF levels induced by TNF-a in endothelial cells (HUVEC) (43). All these data provide evidence that agonists of the EP 1 receptor promote TF activity in endothelial cells and that only the inhibition of EP 1 receptors prevents TF activity induced by CS, showing a link between PGE 2 / EP 1 receptor and TF, and consequently, with thrombosis.…”

Section: Discussionsupporting

confidence: 93%

Production of prostaglandin E₂induced by cigarette smoke modulates tissue factor expression and activity in endothelial cells

Amadio¹,

Baldassarre²,

Tarantino³

et al. 2015

The FASEB Journal

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Cigarette smoke (CS) increases the incidence of atherothrombosis, the release of prostaglandin (PG) E2, and the amount of tissue factor (TF). The link between PGE2 and TF, and the impact of this interaction on CS‐induced thrombosis, is unknown. Plasma from active smokers showed higher concentration of PGE2, TF total antigen, and microparticle‐associated TF (MP‐TF) activity compared with never smokers. Similar results were obtained in mice and in mouse cardiac endothelial cells (MCECs) after treatment with aqueous CS extracts (CSEs) plus IL‐1β [CSE (6.4 puffs/L)/IL‐1β (2 μg/L)]. A significant correlation between PGE2 and TF total antigen or MP‐TF activity were observed in both human and mouse plasma or tissue. Inhibition of PGE synthase reduced TF in vivo and in vitro and prevented the arterial thrombosis induced by CSE/IL‐1β. Only PG E receptor 1 (EP1) receptor antagonists (SC51089:IC5o ~ 1 μM, AH6809:IC5o ~ 7.5 μM) restored the normal TF and sirtuin 1 (SIRT1) levels in MCECs before PGE2 (EC50 ~ 2.5 mM) or CSE/IL‐1β exposure. Similarly, SIRT1 activators (CAY10591: IC50 ~ 10 μM, resveratrol: IC50 ~ 5 μM) or prostacyclin analogs (IC50 ~ 5 μM) prevented SIRT1 inhibition and reduced TF induced by CSE/IL‐1β or by PGE2. In conclusion, PGE2 increases both TF expression and activity through the regulation of the EP1/SIRT1 pathway. These findings suggest that EP1 may represent a possible target to prevent prothrombotic states.—Amadio, P., Baldassarre, D., Tarantino, E., Zacchi, E., Gianellini, S., Squellerio, L., Amato, M., Weksler, B. B., Tremoli, E., Barbieri, S. S. Production of prostaglandin E2 induced by cigarette smoke modulates tissue factor expression and activity in endothelial cells. FASEB J. 29, 4001‐4010 (2015). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 93%

Production of prostaglandin E₂induced by cigarette smoke modulates tissue factor expression and activity in endothelial cells

Amadio¹,

Baldassarre²,

Tarantino³

et al. 2015

The FASEB Journal

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“…The sustained elevation of SBP observed in celecoxib‐treated WT mice may be due to the reduction of PGI 2 (40). It has been reported that both celecoxib and rofecoxib reduced urinary PGI 2 levels in healthy volunteers (41, 42), COX‐2 inhibition by SC58236 or gene disruption in mice completely blocked the Ang II‐induced increase in renal medullary 6‐keto‐PGF 1α (40), and celecoxib inhibited cytokine‐induced 6‐keto‐PGF 1α production in HUVECs (43). Similarly, our results show that celecoxib blocked the Ang II‐induced increase in both of PGE 2 and 6‐keto‐PGF 1α in kidney and aorta.…”

Section: Discussionmentioning

confidence: 99%

Effect of sphingosine kinase 1 inhibition on blood pressure

et al. 2012

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Accumulating evidence suggests that sphingosine kinase 1 (SphK1) plays a key role in carcinogenesis by regulating cyclooxygenase-2 (COX-2) expression. Recent clinical studies have revealed that COX-2 inhibitors cause adverse cardiovascular side effects, likely due to inhibition of prostacyclin (PGI(2)). In this work, we investigated the roles of SphK1 inhibition on blood pressure (BP). The results show that lack of SphK1 expression did not exacerbate angiotensin II (Ang II)-induced acute hypertension, whereas celecoxib, a COX-2 inhibitor, augmented and sustained higher BP in mice. Interestingly, SphK1-knockout mice inhibited prostaglandin E(2) (PGE(2)) but not PGI(2) production in response to Ang II, whereas celecoxib blocked both PGE(2) and PGI(2) production. Mechanistically, SphK1 down-regulation by siRNA in human umbilical vein endothelial cells decreased cytokine-induced PGE(2) production primarily through inhibition of microsomal PGE synthase-1 (mPGES-1), not COX-2. SphK1 down-regulation also decreased MKK6 expression, which phosphorylates and activates P38 MAPK, which, in turn, regulates early growth response-1 (Egr-1), a transcription factor of mPGES-1. Together, these data indicate that SphK1 regulates PGE(2) production by mPGES-1 expression via the p38 MAPK pathway, independent of COX-2 signaling, in endothelial cells, suggesting that SphK1 inhibition may be a promising strategy for cancer chemoprevention with lack of the adverse cardiovascular side effects associated with coxibs.

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“…14 The EP4 antagonist was found to be more effective at reducing polyp size, whereas the EP1 antagonist was more effective at reducing polyp number. 14 Targeting the EP1 receptor was also shown not to affect prostacyclin production in human endothelial cells, 15 important given that inhibition of prostacyclin production by COX-2 selective inhibitors was shown to be one of the major contributors to the cardiovascular side effects of these drugs. 16 Despite these promising findings, the mechanisms by which the EP1 receptor promotes tumorigenesis are unclear.…”

mentioning

confidence: 99%

Targeting the EP1 receptor reduces Fas ligand expression and increases the antitumor immune response in an in vivo model of colon cancer

O'Callaghan

Ryan

Neary

et al. 2013

Intl Journal of Cancer

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Despite studies demonstrating that inhibition of cyclooxygenase-2 (COX-2)-derived prostaglandin E 2 (PGE 2 ) has significant chemotherapeutic benefits in vitro and in vivo, inhibition of COX enzymes is associated with serious gastrointestinal and cardiovascular side effects, limiting the clinical utility of these drugs. PGE 2 signals through four different receptors (EP1-EP4) and targeting individual receptor(s) may avoid these side effects, while retaining significant anticancer benefits. Here, we show that targeted inhibition of the EP1 receptor in the tumor cells and the tumor microenvironment resulted in the significant inhibition of tumor growth in vivo. Both dietary administration and direct injection of the EP1 receptor-specific antagonist, ONO-8713, effectively reduced the growth of established CT26 tumors in BALB/c mice, with suppression of the EP1 receptor in the tumor cells alone less effective in reducing tumor growth. This antitumor effect was associated with reduced Fas ligand expression and attenuated tumor-induced immune suppression. In particular, tumor infiltration by CD4 1 CD25 1 Foxp3 1 regulatory T cells was decreased, whereas the cytotoxic activity of isolated splenocytes against CT26 cells was increased. F4/80 1 macrophage infiltration was also decreased; however, there was no change in macrophage phenotype. These findings suggest that the EP1 receptor represents a potential target for the treatment of colon cancer.Numerous studies have demonstrated a link between chronic inflammation and cancer. One such inflammatory mediator is prostaglandin E 2 (PGE 2 ). 1 PGE 2 is derived from arachidonic acid as a result of the activity of cyclooxygenases (COXs). Numerous mouse models of cancer have demonstrated that COX-2-derived PGE 2 promotes tumor growth, 2,3 with increased expression of COX-2 and PGE 2 being found in various human malignancies. Moreover, inhibition of COX-2-derived PGE 2 has significant chemotherapeutic benefits in vitro and in vivo. 1,4-7 However, despite these anticancer benefits, inhibition of COX enzymes has been found to be associated with serious gastrointestinal and cardiovascular side effects, 4,7 limiting the clinical utility of these drugs.PGE 2 activates four different G-protein-coupled receptors, EP1, EP2, EP3 and EP4, with targeting of the receptors offering the potential of antineoplastic activity with fewer side effects. Although most studies to date have identified the EP2 and EP4 receptors as being responsible for the tumor-promoting effects of PGE 2 , 8 the EP1 receptor may also be an effective target against colon cancer. Human colon cancer cells express the EP1 receptor in vivo, 9,10 whereas EP1 receptor knockout mice have significantly fewer azoxymethane (AOM)-induced aberrant crypt foci 11 (ACF) and colon cancer development. 12 Furthermore, ONO-8711, a selective EP1 antagonist, significantly reduced AOM-induced ACF and intestinal polyp formation in APC Min mice. 11,13 Moreover, Kitamura et al. 14 showed that the EP1 and EP4 receptor subtypes may have separat...

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Inhibition of prostaglandin E2 signaling through the EP1 receptor does not affect prostacyclin production in human endothelial cells

Cited by 9 publications

References 20 publications

Production of prostaglandin E₂induced by cigarette smoke modulates tissue factor expression and activity in endothelial cells

Production of prostaglandin E₂induced by cigarette smoke modulates tissue factor expression and activity in endothelial cells

Effect of sphingosine kinase 1 inhibition on blood pressure

Targeting the EP1 receptor reduces Fas ligand expression and increases the antitumor immune response in an in vivo model of colon cancer

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Inhibition of prostaglandin E2 signaling through the EP1 receptor does not affect prostacyclin production in human endothelial cells

Cited by 9 publications

References 20 publications

Production of prostaglandin E2induced by cigarette smoke modulates tissue factor expression and activity in endothelial cells

Production of prostaglandin E2induced by cigarette smoke modulates tissue factor expression and activity in endothelial cells

Effect of sphingosine kinase 1 inhibition on blood pressure

Targeting the EP1 receptor reduces Fas ligand expression and increases the antitumor immune response in an in vivo model of colon cancer

Contact Info

Product

Resources

About

Production of prostaglandin E₂induced by cigarette smoke modulates tissue factor expression and activity in endothelial cells

Production of prostaglandin E₂induced by cigarette smoke modulates tissue factor expression and activity in endothelial cells