Upregulation of Epac-1 in Hepatic Stellate Cells by Prostaglandin E2 in Liver Fibrosis Is Associated with Reduced Fibrogenesis
| Autor: | Catharina Reker-Smit, Martina Schmidt, Bing Han, Pablo Muñoz-Llancao, Klaas Poelstra, Leonie Beljaars, Sophie Lotersztajn, Eduard Post, Marlies Schippers |
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| Přispěvatelé: | Nanomedicine & Drug Targeting, Groningen Research Institute of Pharmacy, Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), Nanotechnology and Biophysics in Medicine (NANOBIOMED), Biopharmaceuticals, Discovery, Design and Delivery (BDDD) |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pharmacology medicine.medical_specialty Niflumic acid CCL4 Biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Endocrinology Downregulation and upregulation In vivo 030220 oncology & carcinogenesis Internal medicine Journal Article medicine Hepatic stellate cell Molecular Medicine Prostaglandin E2 Protein kinase A Rho-associated protein kinase medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics, 363(2), 126-135. WILLIAMS & WILKINS |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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