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Microsomal prostaglandin E synthase-2 is not essential for in vivo prostaglandin E2 biosynthesis.

ABSTRACT: Prostaglandin E(2) (PGE(2)) plays an important role in the normal physiology of many organ systems. Increased levels of this lipid mediator are associated with many disease states, and it potently regulates inflammatory responses. Three enzymes capable of in vitro synthesis of PGE(2) from the cyclooxygenase metabolite PGH(2) have been described. Here, we examine the contribution of one of these enzymes to PGE(2) production, mPges-2, which encodes microsomal prostaglandin synthase-2 (mPGES-2), by generating mice homozygous for the null allele of this gene. Loss of mPges-2 expression did not result in a measurable decrease in PGE(2) levels in any tissue or cell type examined from healthy mice. Taken together, analysis of the mPGES-2 deficient mouse lines does not substantiate the contention that mPGES-2 is a PGE(2) synthase.

SUBMITTER: Jania LA

PROVIDER: S-EPMC3182462 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Microsomal prostaglandin E synthase-2 is not essential for in vivo prostaglandin E2 biosynthesis.

Jania Leigh A LA Chandrasekharan Subhashini S Backlund Michael G MG Foley Nicholas A NA Snouwaert John J Wang I-Ming IM Clark Patsy P Audoly Laurent P LP Koller Beverly H BH

Prostaglandins & other lipid mediators 20081101 3-4

Prostaglandin E(2) (PGE(2)) plays an important role in the normal physiology of many organ systems. Increased levels of this lipid mediator are associated with many disease states, and it potently regulates inflammatory responses. Three enzymes capable of in vitro synthesis of PGE(2) from the cyclooxygenase metabolite PGH(2) have been described. Here, we examine the contribution of one of these enzymes to PGE(2) production, mPges-2, which encodes microsomal prostaglandin synthase-2 (mPGES-2), by ...[more]

PMID: 19010439

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Microsomal prostaglandin E synthase type 2 (mPGES2) is a glutathione-dependent heme protein, and dithiothreitol dissociates the bound heme to produce active prostaglandin E2 synthase in vitro.

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| S-EPMC3617259 | biostudies-literature

Protective Role of mPGES-1 (Microsomal Prostaglandin E Synthase-1)-Derived PGE2 (Prostaglandin E2) and the Endothelial EP4 (Prostaglandin E Receptor) in Vascular Responses to Injury.

Project description: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.

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Project description: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 (PGI(2)) and PGE(2). Therefore, the challenge remains to identify a mechanism whereby PGI(2) and PGE(2) 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 PGI(2), 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. PGE(2) 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 PGE(2) expression, augmented PGI(2) 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 PGE(2), while avoiding the adverse cardiovascular consequences associated with PGHS-2-mediated PGI(2) suppression.

| S-EPMC1435722 | biostudies-literature

Inhibition of microsomal prostaglandin E2 synthase reduces collagen deposition in melanoma tumors and may improve immunotherapy efficacy by reducing T cell exhaustion

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2023-07-02 | GSE236204 | GEO

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