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Prostaglandin E 2 induces contraction of liver myofibroblasts by activating EP 3 and FP prostanoid receptors
Author(s) -
Ayabe S,
Murata T,
Maruyama T,
Hori M,
Ozaki H
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2008.00051.x
Subject(s) - protein kinase c , contraction (grammar) , medicine , prostanoid , endocrinology , receptor , prostaglandin e , prostaglandin , chemistry , agonist , prostaglandin e2 receptor , rottlerin , microbiology and biotechnology , phosphorylation , biology , biochemistry
Background and purpose: Increased portal pressure in liver injury results from hypercontraction of perivascular non‐parenchymal cells including liver myofibroblasts (MFs). Prostaglandin E 2 (PGE 2 ) 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 Ca 2+ concentration ([Ca 2+ ] i ). Phosphorylation of protein kinase C (PKC) was detected by Western blot analysis. Key results: Liver MFs expressed mRNAs for all four EP receptors. PGE 2 induced contraction in a dose‐ and time‐dependent manner, and slightly increased [Ca 2+ ] i only at high concentrations (10 µmol·L −1 ). An agonist selective for EP 3 receptors, ONO‐AE‐248, dose‐dependently induced MF contraction but did not increase [Ca 2+ ] i . Pretreatment with rottlerin (a specific novel PKC inhibitor) and Ro 31‐8425 (a general PKC inhibitor) significantly reduced 1 µmol·L −1 PGE 2 ‐ or ONO‐AE‐248‐induced contractions. Furthermore, 1 µmol·L −1 PGE 2 stimulated phosphorylation of PKC isoforms PKCδ and PKCε. The F prostanoid (FP) receptor antagonist AL8810 abolished the [Ca 2+ ] i elevation and the rapid contraction induced by 10 µmol·L −1 PGE 2 . Conclusions and implications: Lower concentrations up to 1 µmol·L −1 of PGE 2 induce liver MF contraction via a [Ca 2+ ] 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.