PT  - JOURNAL ARTICLE
AU  - Vedrana Reichenbach
AU  - Josefa Ros
AU  - Guillermo Fernández-Varo
AU  - Gregori Casals
AU  - Pedro Melgar-Lesmes
AU  - Teresa Campos
AU  - Alexandros Makriyannis
AU  - Manuel Morales-Ruiz
AU  - Wladimiro Jiménez
TI  - Prevention of Fibrosis Progression in CCl<sub>4</sub>-Treated Rats: Role of the Hepatic Endocannabinoid and Apelin Systems
AID  - 10.1124/jpet.111.188078
DP  - 2012 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 629--637
VI  - 340
IP  - 3
4099  - http://jpet.aspetjournals.org/content/340/3/629.short
4100  - http://jpet.aspetjournals.org/content/340/3/629.full
SO  - J Pharmacol Exp Ther2012 Mar 01; 340
AB  - Endocannabinoids behave as antifibrogenic agents by interacting with cannabinoid CB2 receptors, whereas the apelin (AP) system acts as a proangiogenic and profibrogenic mediator in the liver. This study assessed the effect of long-term stimulation of CB2 receptors or AP receptor (APJ) blockade on fibrosis progression in rats under a non-discontinued fibrosis induction program. The study was performed in control and CCl4-treated rats for 13 weeks. Fibrosis-induced rats received a CB2 receptor agonist (R,S)-3-(2-iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole (AM1241) (1 mg/kg b.wt.), an APJ antagonist [Ala13]-apelin-13 sequence: Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Ala (F13A) (75 μg/kg b.wt.), or vehicle daily during the last 5 weeks of the CCl4 inhalation program. Mean arterial pressure (MAP), portal pressure (PP), hepatic collagen content, angiogenesis, cell infiltrate, and mRNA expression of a panel of fibrosis-related genes were measured in all animals. Fibrosis-induced rats showed increased hepatic collagen content, reduced MAP, portal hypertension, and increased expression of the assessed messengers in comparison with control rats. However, fibrotic rats treated with either AM1241 or F13A had reduced hepatic collagen content, improved MAP and PP, ameliorated cell viability, and reduced angiogenesis and cell infiltrate compared with untreated fibrotic rats. These results were associated with attenuated induction of platelet-derived growth factor receptor β, α-smooth muscle actin, matrix metalloproteinases, and tissue inhibitors of matrix metalloproteinase. CB2 receptor stimulation or APJ blockade prevents fibrosis progression in CCl4-treated rats. The mechanisms underlying these phenomena are coincident despite the marked dissimilarities between the CB2 and APJ signaling pathways, thus opening new avenues for preventing fibrosis progression in liver diseases.