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Prostaglandin E2 induces contraction of liver myofibroblasts by activating EP3 and FP prostanoid receptors.

Authors: Ayabe, S  Murata, T  Maruyama, T  Hori, M  Ozaki, H 
Citation: Ayabe S, etal., Br J Pharmacol. 2009 Mar;156(5):835-45. doi: 10.1111/j.1476-5381.2008.00051.x. Epub 2009 Feb 23.
Pubmed: (View Article at PubMed) PMID:19239477
DOI: Full-text: DOI:10.1111/j.1476-5381.2008.00051.x

BACKGROUND AND PURPOSE: Increased portal pressure in liver injury results from hypercontraction of perivascular non-parenchymal cells including liver myofibroblasts (MFs). Prostaglandin E2 (PGE2) is the major eicosanoid which is released around the venous system during liver injury, but little is known about their contractile effect on MFs. EXPERIMENTAL APPROACH: Contraction of primary rat liver MFs was measured by a collagen gel contraction assay. Expression of E prostanoid (EP) receptor subtypes was assessed by reverse transcription-polymerase chain reaction. Fura-2 fluorescence was used to determine intracellular Ca2+ concentration ([Ca2+](i)). Phosphorylation of protein kinase C (PKC) was detected by Western blot analysis. KEY RESULTS: Liver MFs expressed mRNAs for all four EP receptors. PGE2 induced contraction in a dose- and time-dependent manner, and slightly increased [Ca2+](i) only at high concentrations (10 micromol.L(-1)). An agonist selective for EP(3) receptors, ONO-AE-248, dose-dependently induced MF contraction but did not increase [Ca2+](i). Pretreatment with rottlerin (a specific novel PKC inhibitor) and Ro 31-8425 (a general PKC inhibitor) significantly reduced 1 micromol.L(-1) PGE(2)- or ONO-AE-248-induced contractions. Furthermore, 1 micromol.L(-1) PGE(2) stimulated phosphorylation of PKC isoforms PKCdelta and PKCepsilon. The F prostanoid (FP) receptor antagonist AL8810 abolished the [Ca(2+)](i) elevation and the rapid contraction induced by 10 micromol.L(-1) PGE2. CONCLUSIONS AND IMPLICATIONS: Lower concentrations up to 1 micromol.L(-1) of PGE2 induce liver MF contraction via a [Ca2+](i)-independent PKC-mediated pathway through the EP(3) receptor, while higher concentrations have an additional pathway leading to Ca(2+)-dependent contraction through activating the FP receptor.

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CRRD Object Information
CRRD ID: 10045899
Created: 2015-06-23
Species: All species
Last Modified: 2015-06-23
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.