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Upregulation of Epac-1 in Hepatic Stellate Cells by Prostaglandin E-2 in Liver Fibrosis Is Associated with Reduced Fibrogenesiss

Schippers, M., Beljaars, L., Post, E., Lotersztajn, S., Reker-Smit, C., Han, B., Llancao, P. A., Schmidt, M. & Poelstra, K., 1-Nov-2017, In : Journal of Pharmacology and Experimental Therapeutics. 363, 2, p. 126-135 10 p.

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  • Upregulation of Epac-1 in Hepatic Stellate Cells by Prostaglandin

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DOI

Exchange protein activated by cAMP (Epac-1) is an important signaling mechanism for cAMP-mediated effects, yet factors that change Epac-1 levels are unknown. Such factors are relevant because it has been postulated that Epac-1 directly affects fibrogenesis. Prostaglandin E-2 (PGE(2)) is a well-known cAMP activator, and we therefore studied the effects of this cyclo-oxygenase product on Epac-1 expression and on fibrogenesis within the liver. Liver fibrosis was induced by 8 weeks carbon tetrachloride (CCL4) administration to mice. In the last 2 weeks, mice received vehicle, PGE(2), the cyclo-oxygenase-2 inhibitor niflumic acid (NFA), or PGE(2) coupled to cell-specific carriers to hepatocytes, Kupffer cells, or hepatic stellate cells (HSC). Results showed antifibrotic effects of PGE(2) and profibrotic effects of NFA in CCL4 mice. Western blot analysis revealed reduced Epac-1 protein expression in fibrotic livers of mice and humans compared with healthy livers. PGE(2) administration to fibrotic mice completely restored intrahepatic Epac-1 levels and also led to reduced Rho kinase activity, a downstream target of Epac-1. Cell-specific delivery of PGE(2) to either hepatocytes, Kupffer cells, or HSC identified the latter cell as the key player in the observed effects on Epac-1 and Rho kinase. No significant alterations in protein kinase A expressions were found. In primary isolated HSC, PGE(2) elicited Rap1 translocation reflecting Epac-1 activation, and Epac-1 agonists attenuated platelet-derived growth factor-induced proliferation and migration of these cells. These studies demonstrate that PGE(2) enhances Epac-1 activity in HSC, which is associated with significant changes in (myo)fibroblast activities in vitro and in vivo. Therefore, Epac-1 is a potential target for antifibrotic drugs.

Original languageEnglish
Pages (from-to)126-135
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume363
Issue number2
Early online date1-Sep-2017
Publication statusPublished - 1-Nov-2017

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  • Journal Article

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