Abstract
Exchange protein activated by cAMP (Epac-1) is an important signaling mechanism for cAMP-mediated effects but factors that change Epac-1 levels are unknown. Such factors are relevant because it has been postulated that Epac-1 directly affects fibrogenesis. Prostaglandin E2 (PGE2) 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 CCL4 administration to mice. In the last 2 weeks, mice received vehicle, PGE2, COX-2 inhibitor Niflumic acid (NFA), or PGE2 coupled to cell-specific carriers to hepatocytes, Kupffer cells or hepatic stellate cells (HSC). Results showed anti-fibrotic effects of PGE2 and pro-fibrotic effects of NFA in CCL4-mice. Western blot analysis revealed reduced Epac-1 protein expression in fibrotic livers of mice and man compared to healthy livers. PGE2 treatment of 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 PGE2 to either hepatocytes, Kupffer cells or hepatic stellate cells identified the latter cell as the mediator for the systemic PGE2 effects on Epac-1. No significant alterations in PKA expressions were found. In primary isolated HSC, PGE2 elicited Rap1 translocation, reflecting Epac-1 activation, and Epac-1 agonists attenuated PDGF-induced proliferation and migration of these cells. These studies demonstrate that altered Epac-1 activity is associated with significant changes in (myo)fibroblast activities in vitro and in vivo, supporting the conclusion that Epac-1 is a potential target for antifibrotic drugs.
- The American Society for Pharmacology and Experimental Therapeutics