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Development of an in vivo active, dual EP1 and EP3 selective antagonist based on a novel acyl sulfonamide bioisostere.
Downey JD, Saleh SA, Bridges TM, Morrison RD, Daniels JS, Lindsley CW, Breyer RM
(2013) Bioorg Med Chem Lett 23: 37-41
MeSH Terms: Animals, Diabetes Mellitus, Half-Life, Humans, Hypertension, Mice, Microsomes, Liver, Pyridines, Receptors, Prostaglandin E, EP1 Subtype, Receptors, Prostaglandin E, EP3 Subtype, Receptors, Thromboxane, Structure-Activity Relationship, Sulfonamides
Show Abstract · Added December 21, 2013
Recent preclinical studies demonstrate a role for the prostaglandin E(2) (PGE(2)) subtype 1 (EP1) receptor in mediating, at least in part, the pathophysiology of hypertension and diabetes mellitus. A series of amide and N-acylsulfonamide analogs of a previously described picolinic acid-based human EP1 receptor antagonist (7) were prepared. Each analog had improved selectivity at the mouse EP1 receptor over the mouse thromboxane receptor (TP). A subset of analogs gained affinity for the mouse PGE(2) subtype 3 (EP3) receptor, another potential therapeutic target. One analog (17) possessed equal selectivity for EP1 and EP3, displayed a sufficient in vivo residence time in mice, and lacked the potential for acyl glucuronide formation common to compound 7. Treatment of mice with 17 significantly attenuated the vasopressor activity resulting from an acute infusion of EP1 and EP3 receptor agonists. Compound 17 represents a potentially novel therapeutic in the treatment of hypertension and diabetes mellitus.
Copyright © 2012 Elsevier Ltd. All rights reserved.
1 Communities
2 Members
0 Resources
13 MeSH Terms
EP1 disruption attenuates end-organ damage in a mouse model of hypertension.
Bartlett CS, Boyd KL, Harris RC, Zent R, Breyer RM
(2012) Hypertension 60: 1184-91
MeSH Terms: Angiotensin II, Animals, Antihypertensive Agents, Aortic Aneurysm, Blood Pressure, Desoxycorticosterone, Disease Models, Animal, Female, Humans, Hydralazine, Hypertension, Kaplan-Meier Estimate, Kidney, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nephrectomy, Receptors, Prostaglandin E, EP1 Subtype
Show Abstract · Added December 21, 2013
Prostaglandin E(2) is a major prostanoid found in the kidney and vasculature contributing to the regulation of blood pressure. The prostaglandin E(2) receptor EP1 has been shown to contribute to hypertension by mediating angiotensin II-dependent vasoconstriction, although its precise role is incompletely characterized. Disruption of the EP1 receptor in C57BL/6J mice reduced the incidence of mortality during severe hypertension induced by uninephrectomy, deoxycorticosterone acetate, and angiotensin II. Mortality was dependent on all components of the model. Death was a result of aortic aneurysm rupture or occurred after development of anasarca, each of which was reduced in EP1-/- mice. Mean arterial pressure was increased in treated EP1+/+ and EP1-/- mice; however, this elevation was significantly lower in EP1-/- mice. Blood pressure reduction via administration of hydralazine phenocopied EP1-/- mice. Thus, reduction in blood pressure by disruption of EP1 reduced incidence of mortality and decreased organ damage, suggesting that EP1 receptor blockade may be a viable target for antihypertensive therapy.
3 Communities
4 Members
0 Resources
19 MeSH Terms
Prostaglandin E2 deficiency uncovers a dominant role for thromboxane A2 in house dust mite-induced allergic pulmonary inflammation.
Liu T, Laidlaw TM, Feng C, Xing W, Shen S, Milne GL, Boyce JA
(2012) Proc Natl Acad Sci U S A 109: 12692-7
MeSH Terms: Allergens, Animals, Antigens, Dermatophagoides, Asthma, Dinoprostone, Intercellular Adhesion Molecule-1, Intramolecular Oxidoreductases, Male, Mice, Mice, Knockout, Pneumonia, Prostaglandin-E Synthases, Pulmonary Eosinophilia, Receptors, Prostaglandin E, EP1 Subtype, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Thromboxane, Signal Transduction, Thromboxane A2, Up-Regulation
Show Abstract · Added March 26, 2014
Prostaglandin E(2) (PGE(2)) is an abundant lipid inflammatory mediator with potent but incompletely understood anti-inflammatory actions in the lung. Deficient PGE(2) generation in the lung predisposes to airway hyperresponsiveness and aspirin intolerance in asthmatic individuals. PGE(2)-deficient ptges(-/-) mice develop exaggerated pulmonary eosinophilia and pulmonary arteriolar smooth-muscle hyperplasia compared with PGE(2)-sufficient controls when challenged intranasally with a house dust mite extract. We now demonstrate that both pulmonary eosinophilia and vascular remodeling in the setting of PGE(2) deficiency depend on thromboxane A(2) and signaling through the T prostanoid (TP) receptor. Deletion of TP receptors from ptges(-/-) mice reduces inflammation, vascular remodeling, cytokine generation, and airway reactivity to wild-type levels, with contributions from TP receptors localized to both hematopoietic cells and tissue. TP receptor signaling ex vivo is controlled heterologously by E prostanoid (EP)(1) and EP(2) receptor-dependent signaling pathways coupling to protein kinases C and A, respectively. TP-dependent up-regulation of intracellular adhesion molecule-1 expression is essential for the effects of PGE(2) deficiency. Thus, PGE(2) controls the strength of TP receptor signaling as a major bronchoprotective mechanism, carrying implications for the pathobiology and therapy of asthma.
1 Communities
1 Members
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19 MeSH Terms
Eicosanoid receptor subtype-mediated opposing regulation of TLR-stimulated expression of astrocyte glial-derived neurotrophic factor.
Li X, Cudaback E, Breyer RM, Montine KS, Keene CD, Montine TJ
(2012) FASEB J 26: 3075-83
MeSH Terms: Animals, Astrocytes, Base Sequence, Cells, Cultured, DNA Primers, Glial Cell Line-Derived Neurotrophic Factor, Immunity, Innate, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, Receptors, Eicosanoid, Receptors, Prostaglandin E, EP1 Subtype, Toll-Like Receptor 2, Toll-Like Receptor 3, Toll-Like Receptor 4, Toll-Like Receptor 9, Toll-Like Receptors
Show Abstract · Added December 21, 2013
A major therapeutic target for Parkinson's disease (PD) is providing increased glial-derived neurotrophic factor (GDNF) to dopaminergic neurons. We tested the hypothesis that innate immune activation increases astrocyte GDNF production and that this is regulated by specific eicosanoid receptors. Innate immune-activated primary murine astrocytes were assayed for GDNF expression and secretion. Controls were agent vehicle exposure and wild-type mice. Rank order for up to 10-fold selectively increased GDNF expression was activators of TLR3 > TLR2 or TLR4 > TLR9. TLR3 activator-stimulated GDNF expression was selectively JNK-dependent, followed cyclooxygenase (COX)-2, was coincident with membranous PGE(2) synthase, and was not significantly altered by a nonspecific COX- or a COX-2-selective inhibitor. Specific eicosanoid receptors had opposing effects on TLR3 activator-induced GDNF expression: ∼60% enhancement by blocking or ablating of PGE(2) receptor subtype 1 (EP1), ∼30% enhancement by activating PGF(2α) receptor or thromboxane receptor, or ∼15% enhancement by activating EP4. These results demonstrate functionally antagonistic eicosanoid receptor subtype regulation of innate immunity-induced astrocyte GDNF expression and suggest that selective inhibition of EP1 signaling might be a means to augment astrocyte GDNF secretion in the context of innate immune activation in diseased regions of brain in PD.
1 Communities
1 Members
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18 MeSH Terms
Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells.
Singh P, Hoggatt J, Hu P, Speth JM, Fukuda S, Breyer RM, Pelus LM
(2012) Blood 119: 1671-82
MeSH Terms: Animals, Cell Differentiation, Cells, Cultured, Dendritic Cells, Dinoprostone, Hematopoietic Stem Cells, Hormone Antagonists, Humans, Infant, Newborn, Inhibitor of Apoptosis Proteins, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Prostaglandin E, EP1 Subtype, Receptors, Prostaglandin E, EP3 Subtype, STAT3 Transcription Factor, Signal Transduction, Survivin
Show Abstract · Added December 21, 2013
Dendritic cell (DC) homeostasis, like all mature blood cells, is maintained via hierarchal generation from hematopoietic precursors; however, little is known about the regulatory mechanisms governing DC generation. Here, we show that prostaglandin E(2) (PGE(2)) is required for optimal Flt3 ligand-mediated DC development and regulates expression of the Flt3 receptor on DC-committed progenitor cells. Inhibition of PGE(2) biosynthesis reduces Flt3-mediated activation of STAT3 and expression of the antiapoptotic protein survivin, resulting in increased apoptosis of DC-committed progenitor cells. Reduced DC development caused by diminished PGE(2) signaling is reversed by overexpression of Flt3 or survivin in DC progenitors and conversely is mimicked by STAT3 inhibition. PGE(2) regulation of DC generation is specifically mediated through the EP1 and EP3 G protein PGE(2) receptors. These studies define a novel DC progenitor regulatory pathway in which PGE(2) signaling through EP1/EP3 receptors regulates Flt3 expression and downstream STAT3 activation and survivin expression, required for optimal DC progenitor survival and DC development in vivo.
1 Communities
1 Members
0 Resources
19 MeSH Terms
Suppressed microglial E prostanoid receptor 1 signaling selectively reduces tumor necrosis factor alpha and interleukin 6 secretion from toll-like receptor 3 activation.
Li X, Cudaback E, Keene CD, Breyer RM, Montine TJ
(2011) Glia 59: 569-76
MeSH Terms: Animals, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Immunity, Innate, Interleukin-6, Mice, Microglia, Receptors, Prostaglandin E, EP1 Subtype, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Toll-Like Receptor 3, Tumor Necrosis Factor-alpha
Show Abstract · Added December 21, 2013
Activation of innate immunity via toll-like receptors (TLRs) is associated with neurodegenerative diseases, and some effectors, like tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6), directly contribute to neurodegeneration. We tested the hypothesis that prostaglandin (PG) E(2) receptor subtype 1 (EP1) was necessary for the induction of microglial cytokines following the activation of innate immunity. Primary murine microglia had cytokine secretion by activators of TLR3 > TLR9 > TLR4 > TLR2. TLR3 activation induced early expression of cyclooxygenase 2 (COX2) and delayed expression of membranous PGE synthase and secretion of PGE(2) . Nonselective and COX2-selective inhibitors blocked TLR3 induction of TNFα and IL-6. Moreover, of the nine of twenty cytokines and chemokines induced by TLR3 activation, only TNFα and IL-6 were significantly dependent on EP1 signaling as determined using microglia from mice homozygous deficient for EP1 gene or wild-type microglia coincubated with an EP1 antagonist. These results were confirmed by blocking intracellular Ca(2+) release with 2-aminoethoxy-diphenyl borate or Xestospongin C, inhibitors of IP3 receptors. Our results show that suppression of microglial EP1 signaling achieves much of the desired effect of COX inhibitors by selectively blocking TLR3-induced microglial secretion of two major effectors of paracrine neuron damage. In combination with the ability of EP1 suppression to ameliorate excitotoxicity, these data point to blockade of EP1 as an attractive candidate therapeutic for neurodegenerative diseases.
Copyright © 2011 Wiley-Liss, Inc.
0 Communities
1 Members
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12 MeSH Terms
Protection of hippocampal neurogenesis from toll-like receptor 4-dependent innate immune activation by ablation of prostaglandin E2 receptor subtype EP1 or EP2.
Keene CD, Chang R, Stephen C, Nivison M, Nutt SE, Look A, Breyer RM, Horner PJ, Hevner R, Montine TJ
(2009) Am J Pathol 174: 2300-9
MeSH Terms: Animals, Fluorescent Antibody Technique, Hippocampus, Immunity, Innate, Lipopolysaccharides, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Neurogenesis, Neurons, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP1 Subtype, Receptors, Prostaglandin E, EP2 Subtype, Reverse Transcriptase Polymerase Chain Reaction, Stem Cells, T-Box Domain Proteins, Toll-Like Receptor 4
Show Abstract · Added December 21, 2013
Prostaglandin E2 is one of several eicosanoid products of the cyclooxygenase isozymes and is a key regulator of innate immune responses; it also possesses paracrine effects on mature neurons. The prostaglandin E2 receptor family consists of four subtypes of which EP1 and EP2 are known to be expressed by microglia. Lipopolysaccharide (LPS)-induced innate immune activation leads to the degeneration of intermediate progenitor cells (IPCs) that are destined for neuronal maturation in the hippocampal subgranular zone (SGZ); these cells can be identified by the expression of the transcription factor T-box brain gene 2 (Tbr2). Importantly, depletion of LPS-induced IPCs from the SGZ is suppressed by cyclooxygenase inhibitors. We therefore tested the hypothesis that either EP1 or EP2 is critical to LPS-induced depletion of Tbr2+ IPCs from the SGZ. Expression of either EP1 or EP2 was necessary for Toll-like receptor 4-dependent innate immune-mediated depletion of these Tbr2+ IPCs in mice. Moreover, EP1 activation was directly toxic to murine adult hippocampal progenitor cells; EP2 was not expressed by these cells. Finally, EP1 modulated the response of murine primary microglia cultures to LPS but in a manner distinct from EP2. These results indicate that prostaglandin E2 signaling via either EP1 or EP2 is largely to completely necessary for Toll-like receptor 4-dependent depletion of IPCs from the SGZ and suggest further pharmacological strategies to protect this important neurogenic niche.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting.
Guan Y, Zhang Y, Wu J, Qi Z, Yang G, Dou D, Gao Y, Chen L, Zhang X, Davis LS, Wei M, Fan X, Carmosino M, Hao C, Imig JD, Breyer RM, Breyer MD
(2007) J Clin Invest 117: 2496-505
MeSH Terms: Angiotensin II, Animals, Base Sequence, Blood Pressure, Dinoprostone, Hypertension, Male, Mice, Mice, Transgenic, Protein Kinase C, Rats, Rats, Inbred SHR, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP1 Subtype
Show Abstract · Added December 21, 2013
Clinical use of prostaglandin synthase-inhibiting NSAIDs is associated with the development of hypertension; however, the cardiovascular effects of antagonists for individual prostaglandin receptors remain uncharacterized. The present studies were aimed at elucidating the role of prostaglandin E2 (PGE2) E-prostanoid receptor subtype 1 (EP1) in regulating blood pressure. Oral administration of the EP1 receptor antagonist SC51322 reduced blood pressure in spontaneously hypertensive rats. To define whether this antihypertensive effect was caused by EP1 receptor inhibition, an EP1-null mouse was generated using a "hit-and-run" strategy that disrupted the gene encoding EP1 but spared expression of protein kinase N (PKN) encoded at the EP1 locus on the antiparallel DNA strand. Selective genetic disruption of the EP1 receptor blunted the acute pressor response to Ang II and reduced chronic Ang II-driven hypertension. SC51322 blunted the constricting effect of Ang II on in vitro-perfused preglomerular renal arterioles and mesenteric arteriolar rings. Similarly, the pressor response to EP1-selective agonists sulprostone and 17-phenyltrinor PGE2 were blunted by SC51322 and in EP1-null mice. These data support the possibility of targeting the EP1 receptor for antihypertensive therapy.
1 Communities
1 Members
0 Resources
14 MeSH Terms
Urine concentrating defect in prostaglandin EP1-deficient mice.
Kennedy CR, Xiong H, Rahal S, Vanderluit J, Slack RS, Zhang Y, Guan Y, Breyer MD, Hébert RL
(2007) Am J Physiol Renal Physiol 292: F868-75
MeSH Terms: Animals, Aquaporin 2, Arginine Vasopressin, Deamino Arginine Vasopressin, Kidney Concentrating Ability, Mice, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP1 Subtype, Water Deprivation
Show Abstract · Added August 13, 2010
We investigated the role of the prostaglandin E(2) (PGE(2)) EP(1) receptor in modulating urine concentration as it is expressed along the renal collecting duct where arginine-vasopressin (AVP) exerts its anti-diuretic activity, and in the paraventricular and supraoptic nuclei of the hypothalamus where AVP is synthesized. The urine osmolality of EP(1)-null mice (EP(1)(-/-)) failed to match levels achieved by wild-type (WT) counterparts upon water deprivation (WD) for 24 h. This difference was reflected by higher plasma osmolality in WD EP(1)(-/-) mice. Along the collecting duct, the induction and subapical to plasma membrane translocation of the aquaporin-2 water channel in WD EP(1)(-/-) mice appeared equivalent to that of WD WT mice as determined by quantitative RT-PCR and immunohistochemistry. However, medullary interstitial osmolalities dropped significantly in EP(1)(-/-) mice following WD. Furthermore, urinary AVP levels of WD EP(1)(-/-) mice were significantly lower than those of WD WT mice. This deficit could be traced back to a blunted induction of hypothalamic AVP mRNA expression in WD EP(1)(-/-) mice as determined by quantitative RT-PCR. Administration of the AVP mimetic [deamino-Cys(1),D-Arg(8)]-vasopressin restored a significant proportion of the urine concentrating ability of WD EP(1)(-/-) mice. When mice were water loaded to suppress endogenous AVP production, urine osmolalities increased equally for WT and EP(1)(-/-) mice. These data suggest that PGE(2) modulates urine concentration by acting at EP(1) receptors, not in the collecting duct, but within the hypothalamus to promote AVP synthesis in response to acute WD.
1 Communities
0 Members
0 Resources
9 MeSH Terms
Prostaglandin EP(1) receptor subtype selectivity takes shape.
Breyer RM
(2001) Mol Pharmacol 59: 1357-9
MeSH Terms: Animals, Dinoprostone, Humans, Receptors, Nicotinic, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP1 Subtype, Structure-Activity Relationship
Added December 21, 2013
0 Communities
1 Members
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7 MeSH Terms