Molecular mechanisms of diverse actions of prostanoid receptors

Negishi, Manabu; Sugimoto, Yukihiko; Ichikawa, Atsushi

doi:10.1016/0005-2760(95)00146-4

Cited by 370 publications

(259 citation statements)

References 72 publications

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“…The molecular mechanisms by which the low concentration of LTB 4 exerts anti-catabolic action against PGE 2 and the potential molecular interplay between PGE 2 and LTB 4 will be of special interest and future studies are required. In addition, it is known that LTB 4 and PGE 2 actions are mediated via their receptors, e.g., BLT1 and BLT2 (Tager and Luster, 2003) and EP1, EP2, EP3, and EP4 (Negishi et al, 1995;Narumiya et al, 1999), respectively. Thus, it is important to investigate the expression and/or activation of their cognate receptors and the signaling pathways for better understanding the precise role of dosedependent counter-activity of LTB 4 on PGE 2 in tendon homeostasis in future studies.…”

Section: Discussionmentioning

confidence: 99%

Leukotriene B4 at low dosage negates the catabolic effect of prostaglandin E2 in human patellar tendon fibroblasts

Thampatty¹,

Im²,

Wang³

2006

Gene

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Tendinopathy often involves inflammation and matrix degeneration. The inflammatory mediators such as prostaglandin E 2 (PGE 2 ) and leukotriene B 4 (LTB 4 ) are implicated in the development of tendinopathy. Therefore, the purpose of this study was to determine the effect of PGE 2 and LTB 4 on the proliferation of human patellar tendon fibroblasts (HPTFs), the gene expression of collagen type I, MMP-1 and MMP-3, as well as the protein secretion of these gene products by the cells. The results showed that LTB 4 at low doses (0.1 and 1 nM) significantly increased cell proliferation compared to controls and LTB 4 at 0.1 nM negated the PGE 2 -induced decrease in cell proliferation. In addition, PGE 2 at 100 ng/ml significantly increased the expression of MMP-1 and MMP-3 at both mRNA and protein levels. These stimulatory effects were significantly diminished by co-treatment with LTB 4 at 0.1 nM. Finally, neither PGE 2 nor LTB 4 treatment affected collagen type I gene expression. These results suggest that low levels of LTB 4 counterbalance the negative effects mediated by PGE 2 on tendon fibroblast proliferation and MMP production, which may lead to matrix degradation. Thus, our findings suggest that although LTB 4 is generally thought to be pathogenic, low levels of LTB 4 are actually beneficial in maintaining tendon tissue homeostasis.

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Section: Discussionmentioning

confidence: 99%

Leukotriene B4 at low dosage negates the catabolic effect of prostaglandin E2 in human patellar tendon fibroblasts

Thampatty¹,

Im²,

Wang³

2006

Gene

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“…Prostaglandin E2 (PGE2) produces a broad range of biological actions in diverse tissues through its binding to specific receptors on plasma membranes [1]. PGE receptors are pharmacologically subdivided into four subtypes, EP1, EP2, EP3, and EP4, on the basis of their responses to various agonists and antagonists [2,3].…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E receptor EP3γ isoform, with mostly full constitutive Gi activity and agonist‐dependent Gs activity

1996

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We recently demonstrated that two exclusively Gicoupled isoforms of the mouse EP3 receptor, EP3a and 13, with different carboxyl-terminal tails, differed in agonist-independent constitutive Gi activity, and the carboxyl-terminal tail-truncated receptor showed full constitutive activity (Hasegawa, H., Negishi, M., and Ichikawa, A. (1996) J. Biol. Chem. 271, 1857-1860). Here we further examined Gi and Gs activities of the third isoform, EP3T, coupled to both Gi and Gs. The EP3 T receptor showed mostly full constitutive Gi activity and agonistdependent Gs activity. The truncated receptor also showed agonist-dependent Gs activity, but the level was lower than that of the EP3T receptor. Thus, the carboxyl-terminal tail would differentially regulate Gi and Gs activities of the EP3 receptor.

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“…TXA 2 is a potent stimulator of platelet aggregation and smooth muscle contraction and may play a role as a mediator of myocardial infarction, atherosclerosis, and bronchial asthma (22). Increased activity of TXA 2 has also been implicated in several forms of human and experimental pulmonary hypertension, including pulmonary hypertension induced by sepsis (36), heparin/protamine (19), and ischemia-reperfusion (39).…”

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confidence: 99%

Cellular mechanisms of thromboxane A₂-mediated contraction in pulmonary veins

Ding¹,

Murray²

2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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[Ca 2ϩ ]i and myofilament Ca 2ϩ sensitivity in the pulmonary venous smooth muscle (PVSM) contractile response to the thromboxane A2 mimetic U-46619 and to assess the roles of PKC, tyrosine kinases (TK), and Rho-kinase (ROK) in that response. We tested the hypothesis that U-46619-induced contraction in PVSM is mediated by both increases in [Ca 2ϩ ]i and myofilament Ca 2ϩ sensitivity and that the PKC, TK, and ROK signaling pathways are involved. Isometric tension was measured in isolated endothelium-denuded (EϪ) canine pulmonary venous (PV) rings. In addition, [Ca 2ϩ ]i and tension were simultaneously measured in fura-2-loaded EϪ PVSM strips. U-46619 (0.1 nM-1 M) caused dose-dependent (P Ͻ 0.001) contraction in PV rings. U-46619 contraction was attenuated by inhibitors of L-type voltage-operated Ca 2ϩ channels (nifedipine, P Ͻ 0.001), inositol 1,4,5-trisphosphate-mediated Ca 2ϩ release (2-aminoethoxydiphenylborate, P Ͻ 0.001), PKC (bisindolylmaleimide I, P Ͻ 0.001), TK (tyrphostin A-47, P ϭ 0.014), and ROK (Y-27632, P ϭ 0.008). In PV strips, U-46619 contraction was associated with increases in [Ca 2ϩ ]i and myofilament Ca 2ϩ sensitivity. Both Ca 2ϩ influx and release mediated the early transient increase in [Ca 2ϩ ]i, whereas the late sustained increase in [Ca 2ϩ ]i only involved Ca 2ϩ influx. Inhibition of both PKC and ROK (P ϭ 0.006 and P ϭ 0.002, respectively), but not TK, attenuated the U-46619-induced increase in myofilament Ca 2ϩ sensitivity. These results suggest that U-46619 contraction is mediated by Ca 2ϩ influx, Ca 2ϩ release, and increased myofilament Ca 2ϩ sensitivity. The PKC, TK, and ROK signaling pathways are involved in U-46619 contraction. pulmonary vein; Ca 2ϩ homeostasis; myofilament Ca 2ϩ sensitivity THROMBOXANE A 2 (TXA 2 ) is a major product of arachidonic acid metabolism via the cyclooxygenase pathway. TXA 2 is a potent stimulator of platelet aggregation and smooth muscle contraction and may play a role as a mediator of myocardial infarction, atherosclerosis, and bronchial asthma (22). Increased activity of TXA 2 has also been implicated in several forms of human and experimental pulmonary hypertension, including pulmonary hypertension induced by sepsis (36), heparin/protamine (19), and ischemia-reperfusion (39).The TXA 2 analog, U-46619, is known to cause constriction of pulmonary veins (13). Pulmonary venous constriction can increase pulmonary capillary pressure and transvascular fluid flux to cause pulmonary edema, which can adversely affect blood oxygenation and right ventricular function. Agonistinduced vascular smooth muscle contraction is mediated by an increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and/or an increase in myofilament Ca 2ϩ sensitivity. We are aware of only one study that has investigated the effects of TXA 2 on [Ca 2ϩ ] i in pulmonary veins (13). In that study, changes in tension in response to the TXA 2 analog, U-46619, were measured in pulmonary venous rings, whereas changes in [Ca 2ϩ ] i were measured separately in dispersed pulmonary venous smo...

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Molecular mechanisms of diverse actions of prostanoid receptors

Cited by 370 publications

References 72 publications

Leukotriene B4 at low dosage negates the catabolic effect of prostaglandin E2 in human patellar tendon fibroblasts

Leukotriene B4 at low dosage negates the catabolic effect of prostaglandin E2 in human patellar tendon fibroblasts

Prostaglandin E receptor EP3γ isoform, with mostly full constitutive Gi activity and agonist‐dependent Gs activity

Cellular mechanisms of thromboxane A₂-mediated contraction in pulmonary veins

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Molecular mechanisms of diverse actions of prostanoid receptors

Cited by 370 publications

References 72 publications

Leukotriene B4 at low dosage negates the catabolic effect of prostaglandin E2 in human patellar tendon fibroblasts

Leukotriene B4 at low dosage negates the catabolic effect of prostaglandin E2 in human patellar tendon fibroblasts

Prostaglandin E receptor EP3γ isoform, with mostly full constitutive Gi activity and agonist‐dependent Gs activity

Cellular mechanisms of thromboxane A2-mediated contraction in pulmonary veins

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Cellular mechanisms of thromboxane A₂-mediated contraction in pulmonary veins