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1.  Enhanced pressor response to acute angiotensin II infusion in mice lacking membrane-associated prostaglandin E2 synthase-1 
Acta pharmacologica Sinica  2010;31(10):1284-1292.
COX-2-mPGES-1-derived prostaglandin E2 (PGE2) plays important roles in regulating vascular tone and renal sodium excretion; however, little is known about the role of mPGES-1 during acute blood pressure regulation. The present study was designed to examine the contribution of vascular mPGES-1 to acute blood pressure homeostasis.
Angiotensin II (AngII, 75 pmol/kg/min) was continuously infused via the jugular vein into wild-type and mPGES-1−/− mice for 30 min, and blood pressure was measured by carotid arterial catheterization. RT-PCR and immunohistochemistry were performed to detect the expression and localization of mPGES-1 in the mouse arterial vessels. Mesenteric arteries were dissected from mice of both genotypes to study vessel tension and measure vascular PGE2 levels.
Wild-type and mPGES-1−/− mice showed similar blood pressure levels at baseline, and the acute intravenous infusion of AngII caused a greater increase in mean arterial pressure in the mPGES-1−/− group, with a similar diuretic and natriuretic response in both groups. mPGES-1 was constitutively expressed in the aortic and mesenteric arteries and vascular smooth muscle cells of wild-type mice. Strong staining was detected in the smooth muscle layer of arterial vessels. Ex vivo treatment of mesenteric arteries with AngII produced more vasodilatory PGE2 in wild-type than in mPGES-1−/− mice. In vitro tension assays further revealed that the mesenteric arteries of mPGES-1−/− mice exhibited a greater vasopressor response to AngII than those arteries of wild-type mice.
Vascular mPGES-1 acts as an important tonic vasodilator, contributing to acute blood pressure regulation.
PMCID: PMC3895497  PMID: 20871624
PGE2; mPGES-1; Angiotensin II; Blood pressure; Resistant vessel
2.  Cell Selective Cardiovascular Biology of Microsomal Prostaglandin E Synthase-1 
Circulation  2012;127(2):233-243.
Global deletion of microsomal prostaglandin E synthase (mPGES) -1 in mice attenuates the response to vascular injury without a predisposition to thrombogenesis or hypertension. However, enzyme deletion results in cell specific differential utilization by prostaglandin (PG) synthases of the accumulated PGH2 substrate. Here, we generated mice deficient in mPGES-1 in vascular smooth muscle cells (VSMCs), endothelial cells (ECs) and myeloid cells further to elucidate the cardiovascular function of this enzyme.
Methods and Results
VSMC and EC mPGES-1 deletion did not alter blood pressure at baseline or in response to a high salt diet. The propensity to evoked macrovascular and microvascular thrombogenesis was also unaltered. However, both VSMC and EC mPGES-1 deficient mice exhibited a markedly exaggerated neointimal hyperplastic response to wire injury of the femoral artery compared to their littermate controls. The hyperplasia was associated with increased proliferating cell nuclear antigen (PCNA) and tenascin-C (TN-C) expression. In contrast, the response to injury was markedly suppressed by myeloid cell depletion of mPGES-1 with decreased hyperplasia, leukocyte infiltration and expression of PCNA and TN-C. Conditioned medium derived from mPGES-1 deficient macrophages less potently induced VSMC proliferation and migration than that from wild type macrophages.
Deletion of mPGES-1 in the vasculature and myeloid cells differentially modulates the response to vascular injury, implicating macrophage mPGES-1 as a cardiovascular drug target.
PMCID: PMC3546279  PMID: 23204105
mPGES-1; vascular injury; vascular smooth muscle cell; endothelial cell; macrophage
3.  Enhanced pressor response to acute Ang II infusion in mice lacking membrane-associated prostaglandin E2 synthase-1 
Acta Pharmacologica Sinica  2010;31(10):1284-1292.
To examine the contribution of vascular membrane-associated prostaglandin E2 synthase-1 (mPGES-1) to acute blood pressure homeostasis.
Angiotensin II (AngII, 75 pmol·kg−1·min−1) was continuously infused via the jugular vein into wild-type and mPGES-1−/− mice for 30 min, and blood pressure was measured by carotid arterial catheterization. RT-PCR and immunohistochemistry were performed to detect the expression and localization of mPGES-1 in the mouse arterial vessels. Mesenteric arteries were dissected from mice of both genotypes to study vessel tension and measure vascular PGE2 levels.
Wild-type and mPGES-1−/− mice showed similar blood pressure levels at baseline, and the acute intravenous infusion of AngII caused a greater increase in mean arterial pressure in the mPGES-1−/− group, with a similar diuretic and natriuretic response in both groups. mPGES-1 was constitutively expressed in the aortic and mesenteric arteries and vascular smooth muscle cells of wild-type mice. Strong staining was detected in the smooth muscle layer of arterial vessels. Ex vivo treatment of mesenteric arteries with AngII produced more vasodilatory PGE2 in wild-type than in mPGES-1−/− mice. In vitro tension assays further revealed that the mesenteric arteries of mPGES-1−/− mice exhibited a greater vasopressor response to AngII than those arteries of wild-type mice.
Vascular mPGES-1 acts as an important tonic vasodilator, contributing to acute blood pressure regulation.
PMCID: PMC3895497  PMID: 20871624
prostaglandin E2; membrane-associated prostaglandin E2 synthase-1; angiotensin II; blood pressure; resistant vessel
4.  Upregulation of Cycolooxygenase-2 (COX-2) and Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) in Wall of Ruptured Human Cerebral Aneurysms: Preliminary Results 
Background and Purpose
Cyclooxygenase-2 (COX-2) and Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) catalyze isomerization of the cyclooxygenase product PGH2 into PGE2. Deletion of COX-2/mPGES-1 suppresses carotid artery atherogenesis, angiotensin II-induced aortic aneurysms formation, and attenuates neointimal hyperplasia after vascular injury in mice. The upregulation of COX-2/mPGES-1 in the wall of ruptured human cerebral aneurysms is not known.
Ten patients with intracranial aneurysms (five ruptured and five non-ruptured) underwent microsurgical clipping. During the procedure, a segment of the aneurysm dome was resected and immunostained with monoclonal antibodies for COX-1, COX2 and mPGES-1. A segment of the superficial temporal artery (STA) was also removed and immunostained with monoclonal antibodies for COX-1, COX2 and mPGES-1.
All ten aneurysm tissues stained positive for mPGES-1 monoclonal antibody. Expression of mPGES-1 was more abundant in ruptured aneurysm tissue than non-ruptured aneurysms, based on a semiquantitative grading. None of the STA specimens expressed mPGES-1. COX-2 was upregulated in the same distribution as mPGES-1. COX-1 was present constitutively in all tissues.
COX-2/mPGES-1 are expressed in the wall of human cerebral aneurysms and more abundantly in ruptured aneurysms than non-ruptured. We speculate that the protective effect of aspirin against rupture of cerebral aneurysms may be mediated in part by inhibition of COX-2/mPGES-1
PMCID: PMC3383865  PMID: 22588264
Aneurysm; mPGES-1; inflammation; COX-2; COX-1
5.  Microsomal Prostaglandin E2 Synthase-1 Modulates the Response to Vascular Injury 
Circulation  2011;123(6):10.1161/CIRCULATIONAHA.110.973685.
Microsomal (m) prostaglandin (PG) E2 synthase (S)-1 catalyzes the formation of PGE2 from PGH2, a cyclooxygenase (COX) product that is derived from arachidonic acid. Previous studies in mice suggest that targeting mPGES-1 may be less likely to cause hypertension or thrombosis than COX-2 selective inhibition or deletion in vivo. Indeed, deletion of mPGES-1 retards atherogenesis and angiotensin II-induced aortic aneurysm formation. The role of mPGES-1 in the response to vascular injury is unknown.
Methods and Results
Mice were subjected to wire injury of the femoral artery. Both neointimal area and vascular stenosis were reduced significantly four weeks after injury in mPGES-1 knock out (KO) mice compared to wild type (WT) controls (65.6±5.7 vs 37.7±5.1×103 pixel area and 70.5±13.4% vs 47.7±17.4%, respectively; p < 0.01). Induction of tenascin C (TN-C) after injury, a pro-proliferative and promigratory extracellular matrix protein, was attenuated in the KOs. Consistent with in vivo rediversion of PG biosynthesis, mPGES-1 deleted vascular smooth muscle cells (VSMC) generated less PGE2, but more PGI2 and expressed reduced TN-C when compared with WT cells. Both suppression of PGE2 and augmentation of PGI2 attenuate TN-C expression, VSMC proliferation and migration in vitro.
Deletion of mPGES-1 in mice attenuates neointimal hyperplasia after vascular injury, in part by regulating TN-C expression. This raises for consideration the therapeutic potential of mPGES-1 inhibitors as adjuvant therapy for percutaneous coronary intervention.
PMCID: PMC3827687  PMID: 21282500
Injury; percutaneous transluminal coronary angioplasty; prostacyclin; prostaglandins; vascular response
6.  Microsomal prostaglandin E synthase-1 in both cancer cells and hosts contributes to tumour growth, invasion and metastasis 
Biochemical Journal  2009;425(Pt 2):361-371.
mPGES-1 (microsomal prostaglandin E synthase-1) is a stimulus-inducible enzyme that functions downstream of COX (cyclo-oxygenase)-2 in the PGE2 (prostaglandin E2)-biosynthesis pathway. Although COX-2-derived PGE2 is known to play a role in the development of various tumours, the involvement of mPGES-1 in carcinogenesis has not yet been fully understood. In the present study, we used LLC (Lewis lung carcinoma) cells with mPGES-1 knockdown or overexpression, as well as mPGES-1-deficient mice to examine the roles of cancer cell- and host-associated mPGES-1 in the processes of tumorigenesis in vitro and in vivo. We found that siRNA (small interfering RNA) silencing of mPGES-1 in LLC cells decreased PGE2 synthesis markedly, accompanied by reduced cell proliferation, attenuated Matrigel™ invasiveness and increased extracellular matrix adhesion. Conversely, mPGES-1-overexpressing LLC cells showed increased proliferating and invasive capacities. When implanted subcutaneously into wild-type mice, mPGES-1-silenced cells formed smaller xenograft tumours than did control cells. Furthermore, LLC tumours grafted subcutaneously into mPGES-1-knockout mice grew more slowly than did those grafted into littermate wild-type mice, with concomitant decreases in the density of microvascular networks, the expression of pro-angiogenic vascular endothelial growth factor, and the activity of matrix metalloproteinase-2. Lung metastasis of intravenously injected LLC cells was also significantly less obvious in mPGES-1-null mice than in wild-type mice. Thus our present approaches provide unequivocal evidence for critical roles of the mPGES-1-dependent PGE2 biosynthetic pathway in both cancer cells and host microenvironments in tumour growth and metastasis.
PMCID: PMC2825730  PMID: 19845504
knockout mouse; metastasis; microsomal prostaglandin E synthase-1; prostaglandin E2; tumorigenesis; COX, cyclo-oxygenase; cPGES, cytosolic prostaglandin E synthase; DMEM, Dulbecco's modified Eagle's medium; dmPGE2, 16,16-dimethyl prostaglandin E2; ECM, extracellular matrix; EP, prostaglandin E receptor; FCS, fetal calf serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HEK, human embryonic kidney; KD, knockdown; KO, knockout; LLC, Lewis lung carcinoma; MMP, matrix metalloproteinase; mPGES, microsomal prostaglandin E synthase; NSAID, non-steroidal anti-inflammatory drug; PG, prostaglandin; PGES, PGE synthase; RT, reverse transcriptase; siRNA, small interfering RNA; TBS, Tris-buffered saline; TBS-Tween, TBS containing 0.05% Tween 20; VEGF, vascular endothelial growth factor; WT, wild-type
7.  Microsomal Prostaglandin E Synthase-1 Inhibits PTEN and Promotes Experimental Cholangiocarcinogenesis and Tumor Progression 
Gastroenterology  2011;140(7):2084-2094.
Background & Aims
Microsomal prostaglandin E synthase-1 (mPGES-1) is a rate-limiting enzyme that is coupled with cyclooxygenase-2 (COX-2) in the synthesis of prostaglandin E2 (PGE2). Although COX-2 is involved in development and progression of various human cancers, the role of mPGES-1 in carcinogenesis has not been determined. We investigated the role of mPGES-1 in human cholangiocarcinoma growth.
We used immunohistochemical analyses to examine the expression of mPGES-1 in formalin-fixed, paraffin-embedded human cholangiocarcinoma tissues. The effects of mPGES-1 on human cholangiocarcinoma cells were determined in vitro and in SCID mice. Immunoblotting and immunoprecipitation assays were performed to determine the levels of PTEN and related signaling molecules in human cholangiocarcinoma cells with overexpression or knockdown of mPGES-1.
mPGES-1 is overexpressed in human cholangiocarcinoma tissues. Overexpression of mPGES-1 in human cholangiocarcinoma cells increased tumor cell proliferation, migration, invasion, and colony formation; in contrast, RNAi knockdown of mPGES-1 inhibited tumor growth parameters. In SCID mice with tumor xenografts, mPGES-1 overexpression accelerated tumor formation and increased tumor weight (P<0.01), whereas mPGES-1 knockdown delayed tumor formation and reduced tumor weight (P<0.01). mPGES-1 inhibited the expression of PTEN, leading to activation of the EGFR–PI3K–AKT–mTOR signaling pathways in cholangiocarcinoma cells. mPGES-1–mediated inhibition of PTEN is regulated through blocking of EGR-1 sumoylation and binding to the 5′-UTR of the PTEN gene.
mPGES-1 promotes experimental cholangiocarcinogenesis and tumor progression by inhibiting PTEN.
PMCID: PMC3109169  PMID: 21354147
cancer cell signaling; biliary tract cancer; bile duct; liver
8.  Shunting of prostanoid biosynthesis in microsomal prostaglandin E synthase-1 null embryo fibroblasts: regulatory effects on inducible nitric oxide synthase expression and nitrite synthesis 
Microsomal postaglandin (PG) E synthase (mPGES)-1 is an inducible enzyme that acts downstream of cyclooxygenase (COX) and specifically catalyzes the conversion of prostaglandin (PG)H2 to PGE2, most prominently in inflammatory conditions. Specific inhibitors of mPGES-1 are not yet available, however, mice with genetic deletion of mPGES-1 have been generated that have given insight into the specific role of mPGES-1 in eicosanoid biosynthesis in vivo and in peritoneal macrophages. We created mouse embryo fibroblast (MEF) cell lines that would facilitate investigation of the effect of mPGES-1 genetic deletion on prostanoid biosynthesis in fibroblast lineage cells and its subsequent effect on the expression of inducible NOS (iNOS) and nitrite biosynthesis using cells derived from mPGES-1 wild-type (WT), heterozygous (Het), and null mice. The results show that genetic deletion of mPGES-1 results in a dramatic decrease in PGE2 production in Het and null MEFs under basal conditions and after stimulation with interleukin (IL)-1β, suggesting that mPGES-1 is critically important for PGE2 production. Furthermore, we show that mPGES-1 gene deletion results in diversion of prostanoid production from PGE2 to 6-keto PGF1α (the stable metabolic product of PGI2; prostacyclin) in a gene dose-dependent manner in Het and null MEFs compared with their WT counterparts, suggesting a shunting phenomenon within the arachidonic acid (AA) metabolic pathway. In addition, we show that mPGES-1 gene deletion and subsequent decrease in PGE2 levels results in a differential induction profile of iNOS and nitrite levels (the stable breakdown product of nitric oxide (NO) in mPGES-1 WT MEFs compared with null MEFs. These results provide important information regarding the therapeutic potential for pharmacologic inhibition of mPGES-1 in inflammatory conditions.—Kapoor, M., Kojima, F., Qian, M., Yang, L., and Crofford, L. J. Shunting of prostanoid biosynthesis in microsomal prostaglandin E synthase-1 null embryo fibroblasts: regulatory effects on inducible nitric oxide synthase expression and nitrite synthesis.
PMCID: PMC4415996  PMID: 17023389
arachidonic acid (AA); cyclooxygenase (COX); L-arginine
9.  Expression and cellular localization of cyclooxygenases and prostaglandin E synthases in the hemorrhagic brain 
Although cyclooxygenases (COX) and prostaglandin E synthases (PGES) have been implicated in ischemic stroke injury, little is known about their role in intracerebral hemorrhage (ICH)-induced brain damage. This study examines the expression and cellular localization of COX-1, COX-2, microsomal PGES-1 (mPGES-1), mPGES-2, and cytosolic PGES (cPGES) in mice that have undergone hemorrhagic brain injury.
ICH was induced in C57BL/6 mice by intrastriatal injection of collagenase. Expression and cellular localization of COX-1, COX-2, mPGES-1, mPGES-2, and cPGES were examined by immunofluorescence staining.
In the hemorrhagic brain, COX-1, mPGES-2, and cPGES were expressed constitutively in neurons; COX-1 was also constitutively expressed in microglia. The immunoreactivity of COX-2 was increased in neurons and astrocytes surrounding blood vessels at 5 h and then tended to decrease in neurons and increase in astrocytes at 1 day. At 3 days after ICH, COX-2 was observed primarily in astrocytes but was absent in neurons. Interestingly, the immunoreactivity of mPGES-1 was increased in neurons in the ipsilateral cortex and astrocytes in the ipsilateral striatum at 1 day post-ICH; the immunoreactivity of astrocytic mPGES-1 further increased at 3 days.
Our data suggest that microglial COX-1, neuronal COX-2, and astrocytic COX-2 and mPGES-1 may work sequentially to affect ICH outcomes. These findings have implications for efforts to develop anti-inflammatory strategies that target COX/PGES pathways to reduce ICH-induced secondary brain damage.
PMCID: PMC3062590  PMID: 21385433
10.  mPGES-1 and prostaglandin E2: vital role in inflammation, hypoxic response, and survival 
Pediatric Research  2012;72(5):460-467.
Apnea associated with infection and inflammation is a major medical concern in preterm infants. Prostaglandin E2 (PGE2) serves as a critical mediator between infection and apnea. We hypothesize that alteration of the microsomal PGE synthase-1 (mPGES-1) PGE2 pathway influences respiratory control and response to hypoxia.
Nine-d-old wild-type (WT) mice, mPGES-1 heterozygote (mPGES-1+/–), and mPGES-1 knockout (mPGES-1–/–) mice were used. Respiration was investigated in mice using flow plethysmography after the mice received either interleukin-1β (IL-1β) (10 µg/kg) or saline. Mice were subjected to a period of normoxia, subsequent exposure to hyperoxia, and finally either moderate (5 min) or severe hypoxia (until 1 min after last gasp).
IL-1β worsened survival in WT mice but not in mice with reduced or no mPGES-1. Reduced expression of mPGES-1 prolonged gasping duration and increased the number of gasps during hypoxia. Response to intracerebroventricular PGE2 was not dependent on mPGES-1 expression.
Activation of mPGES-1 is involved in the rapid and vital response to severe hypoxia as well as inflammation. Attenuation of mPGES-1 appears to have no detrimental effects, yet prolongs autoresuscitation efforts and improves survival. Consequently, inhibition of the mPGES-1 pathway may serve as a potential therapeutic target for the treatment of apnea and respiratory disorders.
PMCID: PMC3647218  PMID: 22926547
11.  mPGES-1 null mice are resistant to bleomycin-induced skin fibrosis 
Microsomal prostaglandin E2 synthase-1 (mPGES-1) is an inducible enzyme that acts downstream of cyclooxygenase (COX) to specifically catalyze the conversion of prostaglandin (PG) H2 to PGE2. mPGES-1 plays a key role in inflammation, pain and arthritis; however, the role of mPGES-1 in fibrogenesis is largely unknown. Herein, we examine the role of mPGES-1 in a mouse model of skin scleroderma using mice deficient in mPGES-1.
Wild type (WT) and mPGES-1 null mice were subjected to the bleomycin model of cutaneous skin scleroderma. mPGES-1 expressions in scleroderma fibroblasts and in fibroblasts derived from bleomycin-exposed mice were assessed by Western blot analysis. Degree of fibrosis, dermal thickness, inflammation, collagen content and the number of α-smooth muscle actin (α-SMA)-positive cells were determined by histological analyses. The quantity of the collagen-specific amino acid hydroxyproline was also measured.
Compared to normal skin fibroblasts, mPGES-1 protein expression was elevated in systemic sclerosis (SSc) fibroblasts and in bleomycin-exposed mice. Compared to WT mice, mPGES-1-null mice were resistant to bleomycin-induced inflammation, cutaneous thickening, collagen production and myofibroblast formation.
mPGES-1 expression is required for bleomycin-induced skin fibrogenesis. Inhibition of mPGES-1 may be a viable method to alleviate the development of cutaneous sclerosis and is a potential therapeutic target to control the onset of fibrogenesis.
PMCID: PMC3546456  PMID: 21266028
12.  Inhibition of microsomal prostaglandin E2 synthase-1 as a molecular basis for the anti-inflammatory actions of boswellic acids from frankincense 
British Journal of Pharmacology  2011;162(1):147-162.
Frankincense, the gum resin derived from Boswellia species, showed anti-inflammatory efficacy in animal models and in pilot clinical studies. Boswellic acids (BAs) are assumed to be responsible for these effects but their anti-inflammatory efficacy in vivo and their molecular modes of action are incompletely understood.
A protein fishing approach using immobilized BA and surface plasmon resonance (SPR) spectroscopy were used to reveal microsomal prostaglandin E2 synthase-1 (mPGES1) as a BA-interacting protein. Cell-free and cell-based assays were applied to confirm the functional interference of BAs with mPGES1. Carrageenan-induced mouse paw oedema and rat pleurisy models were utilized to demonstrate the efficacy of defined BAs in vivo.
Human mPGES1 from A549 cells or in vitro-translated human enzyme selectively bound to BA affinity matrices and SPR spectroscopy confirmed these interactions. BAs reversibly suppressed the transformation of prostaglandin (PG)H2 to PGE2 mediated by mPGES1 (IC50 = 3–10 µM). Also, in intact A549 cells, BAs selectively inhibited PGE2 generation and, in human whole blood, β-BA reduced lipopolysaccharide-induced PGE2 biosynthesis without affecting formation of the COX-derived metabolites 6-keto PGF1α and thromboxane B2. Intraperitoneal or oral administration of β-BA (1 mg·kg−1) suppressed rat pleurisy, accompanied by impaired levels of PGE2 and β-BA (1 mg·kg−1, given i.p.) also reduced mouse paw oedema, both induced by carrageenan.
Suppression of PGE2 formation by BAs via interference with mPGES1 contribute to the anti-inflammatory effectiveness of BAs and of frankincense, and may constitute a biochemical basis for their anti-inflammatory properties.
PMCID: PMC3012413  PMID: 20840544
inflammation; prostaglandin; boswellic acid; microsomal prostaglandin E2 synthase; arachidonic acid
13.  Microsomal prostaglandin E synthase-1 and cyclooxygenase-2 are both required for ischaemic excitotoxicity 
British Journal of Pharmacology  2010;159(5):1174-1186.
Background and purpose:
Although both microsomal prostaglandin E synthase (mPGES)-1 and cyclooxygenase (COX)-2 are critical factors in stroke injury, but the interactions between these enzymes in the ischaemic brain is still obscure. This study examines the hypothesis that mPGES-1 activity is required for COX-2 to cause neuronal damage in ischaemic injury.
Experimental approach:
We used a glutamate-induced excitotoxicity model in cultures of rat or mouse hippocampal slices and a mouse middle cerebral artery occlusion-reperfusion model in vivo. The effect of a COX-2 inhibitor on neuronal damage in mPGES-1 knockout (KO) mice was compared with that in wild-type (WT) mice.
Key results:
In rat hippocampal slices, glutamate-induced excitotoxicity, as well as prostaglandin (PG) E2 production and PGES activation, was significantly attenuated by either MK-886 or NS-398, inhibitors of mPGES-1 and COX-2 respectively; however, co-application of these inhibitors had neither an additive nor a synergistic effect. The protective effect of NS-398 on the excitotoxicity observed in WT slices was completely abolished in mPGES-1 KO slices, which showed less excitotoxicity than WT slices. In the transient focal ischaemia model, mPGES-1 and COX-2 were co-localized in the infarct region of the cortex. Injection of NS-398 reduced not only ischaemic PGE2 production, but also ischaemic injuries in WT mice, but not in mPGES-1 KO mice, which showed less dysfunction than WT mice.
Conclusion and implications:
Microsomal prostaglandin E synthase-1 and COX-2 are co-induced by excess glutamate in ischaemic brain. These enzymes are co-localized and act together to exacerbate stroke injury, by excessive PGE2 production.
PMCID: PMC2839275  PMID: 20128796
prostaglandin E2; prostaglandin E synthase; cyclooxygenase; ischaemia; excitotoxicity; glutamate; inflammation; stroke
14.  Genetic deletion of mPGES-1 abolishes PGE2 production in murine dendritic cells and alters the cytokine profile, but does not affect maturation or migration 
We undertook this study to determine the role of microsomal PGE synthase-1 (mPGES-1) and mPGES-1-generated prostaglandin (PG) E2 on dendritic cell (DC) phenotype and function. Using mPGES-1 knockout (KO) mice, we generated bone marrow derived DCs and determined their eicosanoid production profile, cell surface marker expression, and cytokine production. We also assessed DC migratory and functional capacity in vivo. Compared to wild-type, mPGES-1 deficient DCs exhibited a markedly attenuated increase in PGE2 production upon LPS stimulation, and displayed preferential shunting towards PGD2 production. mPGES-1 KO DCs did not display deficiencies in maturation, migration or ability to sensitize T cells. However, mPGES-1 deficient DCs generated reduced amounts of the Th1 cytokine IL-12, which may in part be due to increased PGD2 rather than decreased PGE2. These findings provide useful information on the effects of inducible PGE2 on the innate immune system, and have important implications regarding potential consequences of pharmacologic mPGES-1 inhibition.
PMCID: PMC3072052  PMID: 21190819
15.  COX-2 but Not mPGES-1 Contributes to Renal PGE2 Induction and Diabetic Proteinuria in Mice with Type-1 Diabetes 
PLoS ONE  2014;9(7):e93182.
Prostaglandin E2 (PGE2) has been implicated to play a pathogenic role in diabetic nephropathy (DN) but its source remains unlcear. To elucidate whether mPGES-1, the best characterized PGE2 synthase, was involved in the development of DN, we examined the renal phenotype of mPGES-1 KO mice subjected to STZ-induced type-1 diabetes. After STZ treatment, mPGES-1 WT and KO mice presented the similar onset of diabetes as shown by similar elevation of blood glucose. Meanwhile, both genotypes of mice exhibited similar increases of urinary and renal PGE2 production. In parallel with this comparable diabetic status, the kidney injury indices including the urinary albumin excretion, kidney weight and the kidney histology (PAS staining) did not show any difference between the two genotypes. By Western-blotting and quantitative qRT-PCR, mPGES-1, mPGES-2, cPGES and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) remain unaltered following six weeks of diabetes. Finally, a selective COX-2 inhibitor celecoxib (50 mg/kg/day) was applied to the STZ-treated KO mice, which resulted in significant reduction of urinary albumin excretion (KO/STZ: 141.5±38.4 vs. KO/STZ + Celebrex: 48.7±20.8 ug/24 h, p<0.05) and the blockade of renal PGE2 induction (kidney: KO/STZ: 588.7±89.2 vs. KO/STZ + Celebrex: 340.8±58.7 ug/24 h, p<0.05; urine: KO/STZ 1667.6±421.4 vs. KO/STZ + Celebrex 813.6±199.9 pg/24 h, p<0.05), without affecting the blood glucose levels and urine volume. Taken together, our data suggests that an as yet unidentified prostaglanind E synthase but not mPGES-1 may couple with COX-2 to mediate increased renal PGE2 sythsesis in DN.
PMCID: PMC4077725  PMID: 24984018
16.  Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function 
Journal of Clinical Investigation  2006;116(5):1391-1399.
We investigated the mechanisms by which inhibitors of prostaglandin G/H synthase-2 (PGHS-2; known colloquially as COX-2) increase the incidence of myocardial infarction and stroke. These inhibitors are believed to exert both their beneficial and their adverse effects by suppression of PGHS-2–derived prostacyclin (PGI2) and PGE2. Therefore, the challenge remains to identify a mechanism whereby PGI2 and PGE2 expression can be suppressed while avoiding adverse cardiovascular events. Here, selective inhibition, knockout, or mutation of PGHS-2, or deletion of the receptor for PGHS-2–derived PGI2, was shown to accelerate thrombogenesis and elevate blood pressure in mice. These responses were attenuated by COX-1 knock down, which mimics the beneficial effects of low-dose aspirin. PGE2 biosynthesis is catalyzed by the coordinate actions of COX enzymes and microsomal PGE synthase-1 (mPGES-1). We show that deletion of mPGES-1 depressed PGE2 expression, augmented PGI2 expression, and had no effect on thromboxane biosynthesis in vivo. Most importantly, mPGES-1 deletion affected neither thrombogenesis nor blood pressure. These results suggest that inhibitors of mPGES-1 may retain their antiinflammatory efficacy by depressing PGE2, while avoiding the adverse cardiovascular consequences associated with PGHS-2–mediated PGI2 suppression.
PMCID: PMC1435722  PMID: 16614756
17.  Microsomal prostaglandin E synthase-1 contributes to ischaemic excitotoxicity through prostaglandin E2 EP3 receptors 
British Journal of Pharmacology  2010;160(4):847-859.
Background and purpose:
Although microsomal prostaglandin E synthase (mPGES)-1 is known to contribute to stroke injury, the underlying mechanisms remain poorly understood. This study examines the hypothesis that EP3 receptors contribute to stroke injury as downstream effectors of mPGES-1 neurotoxicity through Rho kinase activation.
Experimental approach:
We used a glutamate-induced excitotoxicity model in cultured rat and mouse hippocampal slices and a mouse middle cerebral artery occlusion–reperfusion model. Effects of an EP3 receptor antagonist on neuronal damage in mPGES-1 knockout (KO) mice was compared with that in wild-type (WT) mice.
Key results:
In cultures of rat hippocampal slices, the mRNAs of EP1–4 receptors were constitutively expressed and only the EP3 receptor antagonist ONO-AE3-240 attenuated and only the EP3 receptor agonist ONO-AE-248 augmented glutamate-induced excitotoxicity in CA1 neurons. Hippocampal slices from mPGES-1 KO mice showed less excitotoxicity than those from WT mice and the EP3 receptor antagonist did not attenuate the excitotoxicity. In transient focal ischaemia models, injection (i.p.) of an EP3 antagonist reduced infarction, oedema and neurological dysfunction in WT mice, but not in mPGES-1 KO mice, which showed less injury than WT mice. EP3 receptor agonist-induced augmentation of excitotoxicity in vitro was ameliorated by the Rho kinase inhibitor Y-27632 and Pertussis toxin. The Rho kinase inhibitor HA-1077 also ameliorated stroke injury in vivo.
Conclusion and implications:
Activity of mPGES-1 exacerbated stroke injury through EP3 receptors and activation of Rho kinase and/or Gi. Thus, mPGES-1 and EP3 receptors may be valuable therapeutic targets for treatment of human stroke.
This article is commented on by Andreasson, pp. 844–846 of this issue. To view this commentary visit
PMCID: PMC2935993  PMID: 20590584
ischaemia; prostaglandin E2; prostaglandin E synthase; mPGES-1; EP3 receptors; Rho kinase; excitotoxicity
18.  Potential roles of microsomal prostaglandin E synthase-1 in rheumatoid arthritis 
Inflammation and regeneration  2011;31(2):157-166.
Rheumatoid arthritis (RA) is a chronic autoimmune disease which primarily affects the synovial joints leading to inflammation, pain and joint deformities. Nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, both of which inhibit cyclooxygenase (COX), have been extensively used for treating RA patients. Prostaglandin E synthase (PGES) is a specific biosynthetic enzyme that acts downstream of COX and converts prostaglandin (PG) H2 to PGE2. Among PGES isozymes, microsomal PGES-1 (mPGES-1) has been shown to be induced in a variety of cells and tissues under inflammatory conditions. The induction of mPGES-1 in the synovial tissue of RA patients is closely associated with the activation of the tissue by proinflammatory cytokines. Although selective mPGES-1 inhibitors have not yet been widely available, mice lacking mPGES-1 (mPGES-1–/– mice) have been generated to evaluate the physiological and pathological roles of mPGES-1 in vivo. Recent studies utilizing mPGES-1–/– mice have demonstrated the significance of mPGES-1 in the process of chronic inflammation and evocation of humoral immune response in autoimmune arthritis models. These recent findings highlight mPGES-1 as a novel therapeutic target for the treatment of autoimmune inflammatory diseases, including RA. Currently, both natural and synthetic chemicals are being tested for inhibition of mPGES-1 activity to produce PGE2. The present review focuses on the recent advances in understanding the role of mPGES-1 in the pathophysiology of RA.
PMCID: PMC3269760  PMID: 22308189
inflammation; microsomal prostaglandin E synthase-1; prostaglandin E2; rheumatoid arthritis; T-cell-dependent humoral immunity
19.  MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer 
Oncotarget  2015;6(12):10284-10296.
Prostaglandin E2 (PGE2) favors multiple aspects of tumor development and immune evasion. Therefore, microsomal prostaglandin E synthase (mPGES-1/-2), is a potential target for cancer therapy. We explored whether inhibiting mPGES-1 in human and mouse models of breast cancer affects tumor-associated immunity. A new model of breast tumor spheroid killing by human PBMCs was developed. In this model, tumor killing required CD80 expression by tumor-associated phagocytes to trigger cytotoxic T cell activation. Pharmacological mPGES-1 inhibition increased CD80 expression, whereas addition of PGE2, a prostaglandin E2 receptor 2 (EP2) agonist, or activation of signaling downstream of EP2 reduced CD80 expression. Genetic ablation of mPGES-1 resulted in markedly reduced tumor growth in PyMT mice. Macrophages of mPGES-1−/− PyMT mice indeed expressed elevated levels of CD80 compared to their wildtype counterparts. CD80 expression in tumor-spheroid infiltrating mPGES-1−/− macrophages translated into antigen-specific cytotoxic T cell activation. In conclusion, mPGES-1 inhibition elevates CD80 expression by tumor-associated phagocytes to restrict tumor growth. We propose that mPGES-1 inhibition in combination with immune cell activation might be part of a therapeutic strategy to overcome the immunosuppressive tumor microenvironment.
PMCID: PMC4496355  PMID: 25871398
prostaglandins; microenvironment; macrophage polarization; costimulation; cytotoxicity
Prostanoids and PGE2 in particular have been long viewed as one of the major mediators of inflammation in arthritis. However, experimental data indicate that PGE2 can serve both pro- and anti-inflammatory functions. We have previously shown (Kojima, F. et al. 2008 J. Immunol. 180, 8361-8368) that microsomal prostaglandin E synthase-1 (mPGES-1) deletion, which regulates PGE2 production, resulted in the suppression of collagen-induced arthritis (CIA) in mice. This suppression was attributable, at least in part, to the impaired generation of type II collagen autoantibodies. In order to examine the function of mPGES-1 and PGE2 in a non-autoimmune form of arthritis, we used the collagen antibody-induced arthritis (CAIA) model in mice deficient in mPGES-1, thereby bypassing the engagement of the adaptive immune response in arthritis development. Here we report that mPGES-1 deletion significantly increased CAIA disease severity. The latter was associated with a significant (~3.6) upregulation of neutrophil, but not macrophage, recruitment to the inflamed joints. The lipidomic analysis of the arthritic mouse paws by quantitative liquid chromatography / tandem mass-spectrometry (LC/MS/MS) revealed a dramatic (~59-fold) reduction of PGE2 at the peak of arthritis. Altogether, this study highlights mPGES-1 and its product PGE2 as important negative regulators of neutrophil-mediated inflammation and suggests that specific mPGES-1 inhibitors may have differential effects on different types of inflammation. Furthermore, neutrophil-mediated diseases could be exacerbated by inhibition of mPGES-1.
PMCID: PMC3897272  PMID: 24055573
Nanohybrids; Room-temperature phosphorescence(RTP); Sensor; Rutin
21.  Genetic Deletion of Microsomal Prostaglandin E Synthase-1 Suppresses Mouse Mammary Tumor Growth and Angiogenesis 
Prostaglandins & other lipid mediators  2013;0:10.1016/j.prostaglandins.2013.04.002.
The cyclooxygenase/prostaglandin (COX/PG) signaling pathway is of central importance in inflammation and neoplasia. COX inhibitors are widely used for analgesia and also have demonstrated activity for cancer prophylaxis. However, cardiovascular toxicity associated with this drug class diminishes their clinical utility and motivates the development of safer approaches both for pain relief and cancer prevention. The terminal synthase microsomal PGE synthase-1 (mPGES-1) has attracted considerable attention as a potential target. Overexpression of mPGES-1 has been observed in both colorectal and breast cancers, and gene knockout and overexpression approaches have established a role for mPGES-1 in gastrointestinal carcinogenesis. Here we evaluate the contribution of mPGES-1 to mammary tumorigenesis using a gene knockout approach. Mice deficient in mPGES-1 were crossed with a strain in which breast cancer is driven by overexpression of human epidermal growth factor receptor 2 (HER2/neu). Loss of mPGES-1 was associated with a substantial reduction in intramammary PGE2 levels, aromatase activity, and angiogenesis in mammary glands from HER2/neu transgenic mice. Consistent with these findings, we observed a significant reduction in multiplicity of tumors ≥1mm in diameter, suggesting that mPGES-1 contributes to mammary tumor growth. Our data identify mPGES-1 as a potential anti-breast cancer target.
PMCID: PMC3830707  PMID: 23624019
Mouse; mPGES-1; breast cancer; aromatase; angiogenesis; PGE2
22.  Defective Generation of a Humoral Immune Response Is Associated with a Reduced Incidence and Severity of Collagen-Induced Arthritis in Microsomal Prostaglandin E Synthase-1 Null Mice1 
Microsomal PGE synthase-1 (mPGES-1) is an inducible enzyme that acts downstream of cyclooxygenase and specifically catalyzes the conversion of PGH2 to PGE2. The present study demonstrates the effect of genetic deletion of mPGES-1 on the developing immunologic responses and its impact on the clinical model of bovine collagen-induced arthritis. mPGES-1 null and heterozygous mice exhibited decreased incidence and severity of arthritis compared with wild-type mice in a gene dose-dependent manner. Histopathological examination revealed significant reduction in lining hyperplasia and tissue destruction in mPGES-1 null mice compared with their wild-type littermates. mPGES-1 deficient mice also exhibited attenuation of mechanical nociception in a gene dose-dependent manner. In addition, mPGES-1 null and heterozygous mice showed a marked reduction of serum IgG against type II collagen (CII), including subclasses IgG1, IgG2a, IgG2b, IgG2c, and IgG3, compared with wild-type mice, which correlated with the reduction in observed inflammatory features. These results demonstrate for the first time that deficiency of mPGES-1 inhibits the development of collagen-induced arthritis, at least in part, by blocking the development of a humoral immune response against type II collagen. Pharmacologic inhibition of mPGES-1 may therefore impact both the inflammation and the autoimmunity associated with human diseases such as rheumatoid arthritis.
PMCID: PMC2435291  PMID: 18523303
23.  Expression of cyclooxygenase 2, microsomal prostaglandin E synthase 1, and EP receptors is increased in rat oesophageal squamous cell dysplasia and Barrett’s metaplasia induced by duodenal contents reflux 
Gut  2004;53(1):27-33.
Background and aim: It is known that bile acids can induce mucosal injury, stimulate cell proliferation, and promote tumorigenesis. A large body of genetic and biochemical evidence indicate that the biosynthetic pathway of prostaglandin E2 (PGE2) may play an important role in human and rodent tumours. Therefore, we examined the expression pattern of cyclooxygenase 1 (COX-1), COX-2, and microsomal prostaglandin E synthase 1 (mPGES-1), as well as EP receptor subtypes in rat oesophageal lesions induced by duodenal contents reflux.
Methods: Oesophagoduodenal anastomosis was performed in rats to induce duodenal contents reflux. We examined histological changes and expression of COX-1, COX-2, mPGES-1, and EP receptor subtypes in the oesophagus by immunohistochemistry and reverse transcription-polymerase chain reaction.
Results: Normal control oesophageal tissues showed COX-1 expression in subepithelial stromal cells, including endothelial cells and muscular cells, and did not reveal expression of COX-2 or mPGES-1. In the case of squamous cell lesions, immunoreactivity of COX-1 was similar to that of normal lesions, and COX-2 was maximally expressed around the vascular papillae of tissues showing dysplasia and surrounding epithelial layer and basal layer. mPGES-1 was highly expressed in stromal cells with COX-2 expression. In the case of Barrett’s oesophagus, COX-2 and mPGES-1 were predominantly in subepithelial stromal cells. mRNA levels of COX-2, mPGES-1, EP2, EP3, and EP4 were higher in the experimental groups than in controls.
Conclusions: We suggest that the biosynthetic pathway of PGE2 may play an important role in oesophageal squamous cell dysplasia and glandular metaplasia induced by duodenal contents reflux.
PMCID: PMC1773937  PMID: 14684572
cyclooxygenase 2; microsomal prostaglandin E synthase 1; EP receptors; squamous cell dysplasia; Barrett’s oesophagus
24.  Understanding Microscopic Binding of Human Microsomal Prostaglandin E Synthase-1 (mPGES-1) Trimer with Substrate PGH2 and Cofactor GSH: Insights from Computational Alanine Scanning and Site-directed Mutagenesis 
The journal of physical chemistry. B  2010;114(16):5605-5616.
Microsomal prostaglandin E synthase-1 (mPGES-1) is an essential enzyme involved in a variety of diseases and is the most promising target for the design of next-generation anti-inflammatory drugs. In order to establish a solid structural base, we recently developed a model of mPGES-1 trimer structure by using available crystal structures of both microsomal glutathione transferase-1 (MGST1) and ba3-cytochrome c oxidase as templates. The mPGES-1 trimer model has been used, in the present study, to examine the detailed binding of mPGES-1 trimer with substrate PGH2 and cofactor GSH. Results obtained from the computational alanine scanning reveal the contribution of each residue at the protein-ligand interaction interface to the binding affinity, and the computational predictions are supported by the data obtained from the corresponding wet experimental tests. We have also compared our mPGES-1 trimer model with other available 3D models, including an alternative homology model and a low-resolution crystal structure, and found that our mPGES-1 trimer model based on the crystal structures of both MGST1 and ba3-cytochrome c oxidase is more reasonable than the other homology model of mPGES-1 trimer constructed by simply using a low-resolution crystal structure of MGST1 trimer alone as a template. The available low-resolution crystal structure of mPGES-1 trimer represents a closed conformation of the enzyme and, thus, is not suitable for studying mPGES-1 binding with ligands. Our mPGES-1 trimer model represents a reasonable open conformation of the enzyme and is, therefore, promising for studying mPGES-1 binding with ligands in future structure-based drug design targeting mPGES-1.
PMCID: PMC2879598  PMID: 20369883
25.  Consequences of altered eicosanoid patterns for nociceptive processing in mPGES-1-deficient mice 
Cyclooxygenase-2 (COX-2)-dependent prostaglandin (PG) E2 synthesis in the spinal cord plays a major role in the development of inflammatory hyperalgesia and allodynia. Microsomal PGE2 synthase-1 (mPGES-1) isomerizes COX-2-derived PGH2 to PGE2. Here, we evaluated the effect of mPGES-1-deficiency on the noci-ceptive behavior in various models of nociception that depend on PGE2 synthesis. Surprisingly, in the COX-2-dependent zymosan-evoked hyperalgesia model, the nociceptive behavior was not reduced in mPGES-1-deficient mice despite a marked decrease of the spinal PGE2 synthesis. Similarly, the nociceptive behavior was unaltered in mPGES-1-deficient mice in the formalin test. Importantly, spinal cords and primary spinal cord cells derived from mPGES-1-deficient mice showed a redirection of the PGE2 synthesis to PGD2, PGF2α and 6-keto-PGF1α (stable metabolite of PGI2). Since the latter prostaglandins serve also as mediators of noci-ception they may compensate the loss of PGE2 synthesis in mPGES-1-deficient mice.
PMCID: PMC3822549  PMID: 18419601
pain; spinal cord; cyclooxygenase; prostaglandin; mPGES-1; hyperalgesia

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