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Chagoya-de Sanchez, V; Hernandez Munoz, R; Macias-Silva, M; Yanez-Maldonado, L; Martinez-Perez, L; Vidrio-Gomez, S; Romero, PC; Aguero, JFC; Perez-Carreon, JI; Velasco-Loyden, G (2010)

PREVENTION OF IN VITRO HEPATIC STELLATE CELLS ACTIVATION BY THE ADENOSINE DERIVATIVE COMPOUND IFC305

BIOCHEM PHARMACOL 80(11):1690-1699
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We have previously shown that adenosine and the aspartate salt of adenosine (IFC305) reverse preestablished CCl4-induced cirrhosis in rats However, their molecular mechanism of action is not clearly understood. Hepatic stellate cells (HSC) play a pivotal role in liver fibrogenesis leading to cirrhosis, mainly through their activation, changing from a quiescent adipogenic state to a proliferative myofibrogenic condition. Therefore, we decided to investigate the effect of IFC305 on primary cultured rat HSC Our results reveal that this compound suppressed the activation of HSC, as demonstrated by the maintenance of a quiescent cell morphology, including lipid droplets content, inhibition of et-smooth muscle actin (alpha-SMA) and collagen alpha 1(I) expression, and up-regulation of MMP-13, Smad7, and PPAR gamma expression, three key antifibrogenic genes Furthermore, IFC305 was able to repress the platelet-derived growth factor (PDGF)-induced proliferation of HSC. This inhibition was independent of adenosine receptors stimulation, instead. IFC305 was incorporated into cells by adenosine transporters and converted to AMP by adenosine kinase. On the other hand, addition of pyrimidine ribonucleoside as undine reversed the suppressive effect of IFC305 on the proliferation and activation of HSC, suggesting that intracellular pyrimidine starvation would be involved in the molecular mechanism of action of IFC305 In conclusion, IFC305 inhibits HSC activation and maintains their quiescence in vitro, these results could explain in part the antifibrotic liver beneficial effect previously described for this compound on the animal model. (C) 2010 Elsevier Inc All rights reserved.