Prevention of in vitro hepatic stellate cells activation by the adenosine derivative compound IFC305.
We have previously shown that adenosine and the aspartate salt of adenosine (IFC305) reverse pre-established CCl(4)-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 α-smooth muscle actin (α-SMA) and collagen α1(I) expression, and up-regulation of MMP-13, Smad7, and PPARγ 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 uridine 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.
Velasco-Loyden
Gabriela
G
Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), México 04510, D.F., Apdo. postal 70-243, Mexico.
Pérez-Carreón
Julio Isael
JI
Agüero
José Fernando Cabello
JF
Romero
Pilar Cabrales
PC
Vidrio-Gómez
Susana
S
Martínez-Pérez
Lidia
L
Yáñez-Maldonado
Lucia
L
Hernández-Muñoz
Rolando
R
Macías-Silva
Marina
M
de Sánchez
Victoria Chagoya
VC
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006131:Growth Inhibitors / Q000494:pharmacology*; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D006131:Growth Inhibitors; C548964:adenosine 2-aminosuccinic acid-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol; D000241:Adenosine