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Antagonism of the Thromboxane-Prostanoid Receptor as a Potential Therapy for Cardiomyopathy of Muscular Dystrophy.
West JD, Galindo CL, Kim K, Shin JJ, Atkinson JB, Macias-Perez I, Pavliv L, Knollmann BC, Soslow JH, Markham LW, Carrier EJ
(2019) J Am Heart Assoc 8: e011902
MeSH Terms: Animals, Bridged Bicyclo Compounds, Heterocyclic, Cardiomyopathies, Disease Models, Animal, Female, Male, Mice, Mice, Inbred mdx, Mice, Knockout, Muscular Dystrophy, Duchenne, Oxazoles, Prostaglandin Antagonists, Random Allocation, Receptors, Thromboxane
Show Abstract · Added March 4, 2020
Background Muscular dystrophy (MD) causes a progressive cardiomyopathy characterized by diffuse fibrosis, arrhythmia, heart failure, and early death. Activation of the thromboxane-prostanoid receptor (TPr) increases calcium transients in cardiomyocytes and is proarrhythmic and profibrotic. We hypothesized that TPr activation contributes to the cardiac phenotype of MD, and that TPr antagonism would improve cardiac fibrosis and function in preclinical models of MD. Methods and Results Three different mouse models of MD (mdx/utrn double knockout, second generation mdx/mTR double knockout, and delta-sarcoglycan knockout) were given normal drinking water or water containing 25 mg/kg per day of the TPr antagonist ifetroban, beginning at weaning. After 6 months (10 weeks for mdx/utrn double knockout), mice were evaluated for cardiac and skeletal muscle function before euthanization. There was a 100% survival rate of ifetroban-treated mice to the predetermined end point, compared with 60%, 43%, and 90% for mdx/utrn double knockout, mdx/mTR double knockout, and delta-sarcoglycan knockout mice, respectively. TPr antagonism improved cardiac output in mdx/utrn double knockout and mdx/mTR mice, and normalized fractional shortening, ejection fraction, and other parameters in delta-sarcoglycan knockout mice. Cardiac fibrosis in delta-sarcoglycan knockout was reduced with TPr antagonism, which also normalized cardiac expression of claudin-5 and neuronal nitric oxide synthase proteins and multiple signature genes of Duchenne MD. Conclusions TPr antagonism reduced cardiomyopathy and spontaneous death in mouse models of Duchenne and limb-girdle MD. Based on these studies, ifetroban and other TPr antagonists could be novel therapeutics for treatment of the cardiac phenotype in patients with MD.
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14 MeSH Terms
Multitargeting of selected prostanoid receptors provides agents with enhanced anti-inflammatory activity in macrophages.
Wang JW, Woodward DF, Martos JL, Cornell CL, Carling RW, Kingsley PJ, Marnett LJ
(2016) FASEB J 30: 394-404
MeSH Terms: Anti-Inflammatory Agents, Non-Steroidal, Bridged Bicyclo Compounds, Heterocyclic, Cells, Cultured, Cinnamates, Humans, Macrophages, Receptors, Prostaglandin, Receptors, Thromboxane, Substrate Specificity
Show Abstract · Added February 22, 2016
A polypharmacologic approach to prostanoid based anti-inflammatory therapeutics was undertaken in order to exploit both the anti- and proinflammatory properties attributed to the various prostanoid receptors. Multitargeting of selected prostanoid receptors yielded a prototype compound, compound 1 (AGN 211377), that antagonizes prostaglandin D2 receptors (DPs) DP1 (49) and DP2 (558), prostaglandin E2 receptors (EPs) EP1 (266) and EP4 (117), prostaglandin F2α receptor (FP) (61), and thromboxane A2 receptor (TP) (11) while sparing EP2, EP3, and prostaglandin I2 receptors (IPs); Kb values (in nanomoles) are given in parentheses. Compound 1 evoked a pronounced inhibition of cytokine/chemokine secretion from lipopolysaccharide or TNF-α stimulated primary human macrophages. These cytokine/chemokines included cluster of designation 40 receptor (CD40), epithelial-derived neutrophil-activating protein 78 (ENA-78), granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), IL-8, IL-18, monocyte chemotactic protein-1 (CCL2) (MCP-1), tissue plasminogen activator inhibitor (PAI-1), and regulated on activation, normal T cell expressed and secreted (RANTES). In contrast, the inhibitory effects of most antagonists selective for a single receptor were modest or absent, and selective EP2 receptor blockade increased cytokine release in some instances. Compound 1 also showed clear superiority to the cyclooxygenase inhibitors diclofenac and rofecoxib. These findings reveal that blockade of multiple prostanoid receptors, with absent antagonism of EP2 and IP, may provide more effective anti-inflammatory activity than global suppression of prostanoid synthesis or highly selective prostanoid receptor blockade. These investigations demonstrate the first working example of prostanoid receptor polypharmacology for potentially safer and more effective anti-inflammatory therapeutics by blocking multiple proinflammatory receptors while sparing those with anti-inflammatory activity.
© FASEB.
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9 MeSH Terms
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.
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13 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
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19 MeSH Terms
Isoprostanes as physiological mediators of transition to newborn life: novel mechanisms regulating patency of the term and preterm ductus arteriosus.
Chen JX, O'Mara PW, Poole SD, Brown N, Ehinger NJ, Slaughter JC, Paria BC, Aschner JL, Reese J
(2012) Pediatr Res 72: 122-8
MeSH Terms: Analysis of Variance, Animals, Animals, Newborn, Bridged Bicyclo Compounds, Heterocyclic, Dinoprost, Dinoprostone, Ductus Arteriosus, Ductus Arteriosus, Patent, Fatty Acids, Unsaturated, Female, Gas Chromatography-Mass Spectrometry, Gene Expression Profiling, Hydrazines, Isoprostanes, Mice, Myography, Oxidative Stress, Oxygen, Pregnancy, Premature Birth, Receptors, Prostaglandin E, EP4 Subtype, Receptors, Thromboxane A2, Prostaglandin H2, Vasodilation
Show Abstract · Added May 26, 2015
BACKGROUND - Increased oxygen tension at birth regulates physiologic events that are essential to postnatal survival, but the accompanying oxidative stress may also generate isoprostanes. We hypothesized that isoprostanes regulate ductus arteriosus (DA) function during postnatal vascular transition.
METHODS - Isoprostanes were measured by gas chromatography-mass spectrometry. DA tone was assessed by pressure myography. Gene expression was measured by quantitative PCR.
RESULTS - Oxygen exposure was associated with increased 8-iso-prostaglandin (PG)F2α in newborn mouse lungs. Both 8-iso-PGE2 and 8-iso-PGF2α induced concentration-dependent constriction of the isolated term DA, which was reversed by the thromboxane A2 (TxA2) receptor antagonist SQ29548. SQ29548 pretreatment unmasked an isoprostane-induced DA dilation mediated by the EP4 PG receptor. Exposure of the preterm DA to 8-iso-PGE2 caused unexpected DA relaxation that was reversed by EP4 antagonism. In contrast, exposure to 8-iso-PGF2α caused preterm DA constriction via TxA2 receptor activation. Further investigation revealed the predominance of the TxA2 receptor at term, whereas the EP4 receptor was expressed and functionally active from mid-gestation onward.
CONCLUSION - This study identifies a novel physiological role for isoprostanes during postnatal vascular transition and provide evidence that oxidative stress may act on membrane lipids to produce vasoactive mediators that stimulate physiological DA closure at birth or induce pathological patency of the preterm DA.
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23 MeSH Terms
Distinct roles for basal and induced COX-2 in podocyte injury.
Cheng H, Fan X, Guan Y, Moeckel GW, Zent R, Harris RC
(2009) J Am Soc Nephrol 20: 1953-62
MeSH Terms: Albuminuria, Animals, Antibiotics, Antineoplastic, Apoptosis, Cell Adhesion, Cell Line, Transformed, Cell Survival, Cyclooxygenase 2, Dinoprostone, Doxorubicin, Glomerulonephritis, Male, Mice, Mice, Inbred Strains, Mice, Transgenic, Podocytes, Puromycin, RNA, Messenger, Receptors, Prostaglandin E, Receptors, Thromboxane, Thromboxanes
Show Abstract · Added December 10, 2013
Transgenic mice that overexpress cyclooxygenase-2 (COX-2) selectively in podocytes are more susceptible to glomerular injury by adriamycin and puromycin (PAN). To investigate the potential roles of COX-2 metabolites, we studied mice with selective deletion of prostanoid receptors and generated conditionally immortalized podocyte lines from mice with either COX-2 deletion or overexpression. Podocytes that overexpressed COX-2 were virtually indistinguishable from wild-type podocytes but were significantly more sensitive to PAN-induced injury, produced more prostaglandin E(2) and thromboxane B(2), and had greater expression of prostaglandin E(2) receptor subtype 4 (EP(4)) and thromboxane receptor (TP). Treatment of COX-2-overexpressing podocytes with a TP antagonist reduced apoptosis, but treatment with an EP(4) antagonist did not. In contrast, podocytes from COX-2-knockout mice exhibited increased apoptosis, markedly decreased cell adhesion, and prominent stress fibers. In vivo, selective deletion of podocyte EP(4) did not alter the increased sensitivity to adriamycin-induced injury observed in mice overexpressing podocyte COX-2. In contrast, genetic deletion of TP in these mice prevented adriamycin-induced injury, with attenuated albuminuria and foot process effacement. These results suggest that basal COX-2 may be important for podocyte survival, but overexpression of podocyte COX-2 increases susceptibility to podocyte injury, which is mediated, in part, by activation of the thromboxane receptor.
2 Communities
3 Members
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21 MeSH Terms
Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation.
Hata AN, Breyer RM
(2004) Pharmacol Ther 103: 147-66
MeSH Terms: Humans, Inflammation, Phylogeny, Prostaglandins, Receptors, Epoprostenol, Receptors, Immunologic, Receptors, Prostaglandin, Receptors, Prostaglandin E, Receptors, Thromboxane A2, Prostaglandin H2
Show Abstract · Added December 21, 2013
Prostaglandins are lipid-derived autacoids that modulate many physiological systems including the CNS, cardiovascular, gastrointestinal, genitourinary, endocrine, respiratory, and immune systems. In addition, prostaglandins have been implicated in a broad array of diseases including cancer, inflammation, cardiovascular disease, and hypertension. Prostaglandins exert their effects by activating rhodopsin-like seven transmembrane spanning G protein-coupled receptors (GPCRs). The prostanoid receptor subfamily is comprised of eight members (DP, EP1-4, FP, IP, and TP), and recently, a ninth prostaglandin receptor was identified-the chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2). The precise roles prostaglandin receptors play in physiologic and pathologic settings are determined by multiple factors including cellular context, receptor expression profile, ligand affinity, and differential coupling to signal transduction pathways. This complexity is highlighted by the diverse and often opposing effects of prostaglandins within the immune system. In certain settings, prostaglandins function as pro-inflammatory mediators, but in others, they appear to have anti-inflammatory properties. In this review, we will discuss the pharmacology and signaling of the nine known prostaglandin GPCRs and highlight the specific roles that these receptors play in inflammation and immune modulation.
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9 MeSH Terms
Endotoxin modulates arachidonic acid-induced glycogenolysis in the perfused rat liver.
Kimura K, Moriyama M, Nishisako M, Kannan Y, Shiota M, Sugano T
(1998) Horm Metab Res 30: 178-81
MeSH Terms: Animals, Arachidonic Acid, Lipopolysaccharides, Liver, Liver Glycogen, Macrophages, Male, Oxygen Consumption, Perfusion, Rats, Rats, Sprague-Dawley, Receptors, Thromboxane
Show Abstract · Added December 10, 2013
Effects of endotoxin on arachidonic acid (AA)-induced hepatic glycogenolysis were examined in perfused rat liver. In normal rat liver, infusion of AA increased oxygen consumption and glucose production concurrently. In rats injected with lipopolysaccharide (LPS) 6 h before, AA increased glucose production but suppressed oxygen consumption. The changes in LPS-injected rat were abolished by a thromboxane (Tx) A2 receptor antagonist. The release of Tx B2 by AA increased after LPS-injection. These results suggest that priming of hepatic macrophage by endotoxin in vivo enhances Tx synthesis, resulting in modulating hepatic glycogenolysis.
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12 MeSH Terms
Modulation of platelet activating factor-induced glycogenolysis in the perfused rat liver after administration of endotoxin in vivo.
Kimura K, Moriyama M, Nishisako M, Kannan Y, Shiota M, Sakurada K, Musashi M, Sugano T
(1998) J Biochem 123: 142-9
MeSH Terms: Animals, Eicosanoids, Endotoxemia, Glycogen, Leukotriene Antagonists, Leukotriene D4, Lipopolysaccharides, Liver, Male, Membrane Proteins, Oxygen Consumption, Perfusion, Platelet Activating Factor, Prostaglandin D2, Rats, Rats, Sprague-Dawley, Receptors, Immunologic, Receptors, Leukotriene, Receptors, Prostaglandin, Receptors, Thromboxane, Thromboxane A2
Show Abstract · Added December 10, 2013
The effect of endotoxin treatment in vivo on platelet activating factor (PAF)-induced glycogenolysis was studied in the perfused rat liver. The addition of PAF (20 nM) to the perfusate increased glucose production concomitant with suppression of oxygen consumption in control rats without endotoxin treatment. At 6 h after endotoxin administration, PAF caused severe suppression of oxygen consumption, but glucose production was greatly inhibited. At 24 h after endotoxin treatment, PAF caused less suppression of oxygen consumption than the control, and glucose production was partially restored. The metabolic responses in the control rat were abolished by the simultaneous presence of cyclooxygenase- and lipoxygenase-inhibitors. Combined use of leukotriene (LT) D4- and thromboxane (Tx) A2-receptor antagonists inhibited the metabolic responses in the rat given endotoxin 6 h before. The efflux of Tx B2 during PAF-infusion decreased 24 h after endotoxin treatment, and Tx A2 receptor antagonist, but not LT D4 receptor antagonist, prevented the suppression of oxygen consumption. These results suggest that different eicosanoids are involved in PAF-induced glycogenolysis in different stages of endotoxemia, and that LT D1 may also play a role in PAF-induced glycogenolysis.
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21 MeSH Terms
Airway and vascular effects of 8-epi-prostaglandin F2 alpha in isolated perfused rat lung.
Kang KH, Morrow JD, Roberts LJ, Newman JH, Banerjee M
(1993) J Appl Physiol (1985) 74: 460-5
MeSH Terms: Air Pressure, Airway Resistance, Animals, Arginine, Atrial Natriuretic Factor, Blood Pressure, Bridged Bicyclo Compounds, Heterocyclic, Dinoprost, Fatty Acids, Unsaturated, Hydrazines, In Vitro Techniques, Lung, Lung Compliance, Microcirculation, Nitroarginine, Pulmonary Circulation, Rats, Rats, Sprague-Dawley, Receptors, Thromboxane, Respiratory Mechanics, Tidal Volume, Vasoconstrictor Agents
Show Abstract · Added December 10, 2013
The effects of 8-epi-prostaglandin (PG) F2 alpha, a recently discovered noncyclooxygenase free radical-catalyzed product of arachidonic acid, on pulmonary vascular and airway tone, its potency, and its mechanism of action were studied. Progressively increasing bolus doses (1.0, 5.0, 10.0, and 20.0 micrograms) of 8-epi-PGF2 alpha were injected into the pulmonary artery catheter of 18 isolated rat lungs, and a single dose (40.0 micrograms) was injected into 7 additional rat lungs. The lungs were perfused with Krebs-Henseleit buffer solution containing 3% bovine serum albumin at 50 ml.kg-1.min-1 during ventilation with 21% O2-5% CO2-74% N2. 8-Epi-PGF2 alpha caused rapid pulmonary vascular and airway constrictor responses, which were followed by a gradual return over 10 min to baseline levels. Double vascular occlusion at peak rise in pulmonary arterial pressure (Ppa) revealed a 28% increase in arterial resistance. The rise in Ppa with 20 micrograms of 8-epi-PGF2 alpha was approximately twofold greater than with 20 micrograms of the cyclooxygenase-derived prostaglandin PGF2 alpha. The addition of 100 microM N-nitro-L-arginine, a blocker of endothelium-derived relaxing factor, in the perfusate potentiated the rise in Ppa by 244%. Injection of 40 micrograms of rat atrial natriuretic factor at peak response to 20 micrograms of 8-epi-PGF2 alpha accelerated the return to baseline Ppa, resistance to airflow across the lung, and dynamic lung compliance values.(ABSTRACT TRUNCATED AT 250 WORDS)
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22 MeSH Terms