Endothelin‐1 Stimulates Sphingosine Kinase in Human Hepatic Stellate Cells: A Novel Role for Sphingosine‐1‐P as a Mediator of Growth Inhibition

Gallois, Cyrille; Davaille, J.; Habib, Aı̈da; Mallat, Ariane; Tao, Jiangchuan; Levade, Thierry; Lotoersztajn, S.

doi:10.1111/j.1749-6632.2000.tb06568.x

Cited by 10 publications

(6 citation statements)

References 16 publications

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“…B). We have previously shown that cAMP mediates PGE 2 induced inhibition of hMF growth [Mallat et al, ; Gallois et al, ]. Treatment of hMF with 10 µM fluvastatin resulted in a significant increase in cAMP formation, which was blocked by ibuprofen, a non‐selective COX‐1/COX‐2 inhibitor, or with NS398, a selective COX‐2 inhibitor (Fig.…”

Section: Resultsmentioning

confidence: 78%

“…We have previously demonstrated the anti‐fibrogenic properties of COX‐2‐derived PGE 2 . Indeed, an increase in PGE 2 in response to various proinflammatory and growth factor factors such as endothelin‐1, TNFα, PDGF or sphingosine‐1‐phosphate results in an increase in cAMP and a reduction of hMF growth, suggesting that factors that induce PGE 2 and COX‐2 in hMF may be interesting as antifibrogenic agents [Gallois et al, , ; Mallat et al, ]. Statins are competitive inhibitors of 3‐hydroxyl‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase that lower circulating LDL.…”

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confidence: 99%

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Statins Modulate Cyclooxygenase‐2 and Microsomal Prostaglandin E Synthase‐1 in Human Hepatic Myofibroblasts

Mouawad

Mrad

El-Achkar

et al. 2015

J of Cellular Biochemistry

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Statins have been shown to exert anti-inflammatory and anti-fibrogenic properties in the liver. In the present study, we explored the mechanisms underlying anti-fibrogenic effects of statins in isolated hepatic myofibroblasts and focused on cyclooxyegnase-2, a major anti-proliferative pathway in these cells. We show that simvastatin and fluvastatin inhibit thymidine incorporation in hMF in a dose-dependent manner. Pretreatment of cells with NS398, a COX-2 inhibitor, partially blunted this effect. cAMP levels, essential to the inhibition of hMF proliferation, were increased by statins and inhibited by non-steroidal anti-inflammatory drugs. Since statins modify prenylation of some important proteins in gene expression, we investigated the targets involved using selective inhibitors of prenyltransferases. Inhibition of geranylgeranylation resulted in the induction of COX-2 and mPGES-1. Using gel retardation assays, we further demonstrated that statins potentially activated the NFκB and CRE/E-box binding for COX-2 promoter and the binding of GC-rich regions and GATA for mPGES-1. Together these data demonstrate that statin limit hepatic myofibroblasts proliferation via a COX-2 and mPGES-1 dependent pathway. These data suggest that statin-dependent increase of prostaglandin in hMF contributes to its anti-fibrogenic effect.

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Section: Resultsmentioning

confidence: 78%

mentioning

confidence: 99%

Statins Modulate Cyclooxygenase‐2 and Microsomal Prostaglandin E Synthase‐1 in Human Hepatic Myofibroblasts

Mouawad

Mrad

El-Achkar

et al. 2015

J of Cellular Biochemistry

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“…Culture studies have shown that endothelin-1 displays dual pro-and antifibrogenic effects in the liver according to receptor subtype: thus, binding of ETA receptors stimulates activation of hepatic stellate cells and induces a weak mitogenic effect. In contrast, binding of ETB receptors promotes marked growth inhibition (28, 81) by a mechanism involving the sequential generation of sphingosine-1-phosphate (S1P), cyclooxygenase-2 (COX-2)-derived prostaglandins, and elevation of cAMP (28, 82,83). Therefore, these results suggested that antifibrotic effects may be achieved by selectively inhibiting ETA receptors, whereas beneficial antifibrogenic effects of ETB receptors should be protected, or even better enhanced.…”

Section: Endothelin-1mentioning

confidence: 79%

HEPATIC FIBROSIS: Molecular Mechanisms and Drug Targets

Lotersztajn

Julien²,

Teixeira-Clerc³

et al. 2005

Annu. Rev. Pharmacol. Toxicol.

286

287

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Liver fibrosis is the common response to chronic liver injury, ultimately leading to cirrhosis and its complications, portal hypertension, liver failure, and hepatocellular carcinoma. Efficient and well-tolerated antifibrotic drugs are currently lacking, and current treatment of hepatic fibrosis is limited to withdrawal of the noxious agent. Efforts over the past decade have mainly focused on fibrogenic cells generating the scarring response, although promising data on inhibition of parenchymal injury and/or reduction of liver inflammation have also been obtained. A large number of approaches have been validated in culture studies and in animal models, and several clinical trials are underway or anticipated for a growing number of molecules. This review highlights recent advances in the molecular mechanisms of liver fibrosis and discusses mechanistically based strategies that have recently emerged.

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“…Furthermore, ET-1 was able to stimulate SphK1 activity and to induce translocation of the enzyme from the cytosol to the membranes. The activation of SphK by ET-1 has also been observed in human hepatic stellate cells (15). In rat myometrium, ET-1 activated SphK1 via ET A receptors coupled to PTX-insensitive G protein.…”

Section: Discussionmentioning

confidence: 92%

Exogenous sphingosine 1-phosphate and sphingosine kinase activated by endothelin-1 induced myometrial contraction through differential mechanisms

Leiber¹,

Banno²,

Tanfin³

2007

American Journal of Physiology-Cell Physiology

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Sphingosine 1-phosphate (S1P), a bioactive sphingolipid involved in diverse biological processes, is generated by sphingosine kinase (SphK) and acts via intracellular and/or extracellular mechanisms. We used biochemical, pharmacological, and physiological approaches to investigate in rat myometrium the contractile effect of exogenous S1P and the possible contribution of SphK in endothelin-1 (ET-1)-mediated contraction. S1P stimulated uterine contractility (EC(50) = 1 microM and maximal response = 5 microM) by a pertussis toxin-insensitive and a phospholipse C (PLC)-independent pathway. Phosphorylated FTY720, which interacts with all S1P receptors, except S1P(2) receptors, failed to mimic S1P contractile response, indicating that the effects of S1P involved S1P(2) receptors that are expressed in myometrium. Contraction mediated by S1P and ET-1 required extracellular calcium and Rho kinase activation. Inhibition of SphK reduced ET-1-mediated contraction. ET-1, via ET(A) receptors coupled to pertussis toxin-insensitive G proteins, stimulated SphK1 activity and induced its translocation to the membranes. Myometrial contraction triggered by ET-1 is consecutive to the sequential activation of PLC, protein kinase C, SphK1 and Rho kinase. Prolonged exposure of the myometrium to S1P downregulated S1P(2) receptors and abolished the contraction induced by exogenous S1P. However, in these conditions, the tension triggered by ET-1 was not reduced, indicating that SphK activated by ET-1 contributed to its contractile effect via a S1P(2) receptor-independent process. Our findings demonstrated that exogenous S1P and SphK activity regulated myometrial contraction and may be of physiological relevance in the regulation of uterine motility during gestation and parturition.

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Endothelin‐1 Stimulates Sphingosine Kinase in Human Hepatic Stellate Cells: A Novel Role for Sphingosine‐1‐P as a Mediator of Growth Inhibition

Cited by 10 publications

References 16 publications

Statins Modulate Cyclooxygenase‐2 and Microsomal Prostaglandin E Synthase‐1 in Human Hepatic Myofibroblasts

Statins Modulate Cyclooxygenase‐2 and Microsomal Prostaglandin E Synthase‐1 in Human Hepatic Myofibroblasts

HEPATIC FIBROSIS: Molecular Mechanisms and Drug Targets

Exogenous sphingosine 1-phosphate and sphingosine kinase activated by endothelin-1 induced myometrial contraction through differential mechanisms

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