Abstract
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.
Footnotes
This work was supported by the Dirección General de Investigación Científica y Técnica [Grants SAF09-08839, SAF07-63069] (to W.J. and M.M.-R., respectively); Agència de Gestió d'Ajuts Universitaris i de Recerca [Grant SGR 2009/1496]; Dirección General de Investigación Científica y Tecnológica [Grant BES-2004-5186] (to P.M.-L.); and Instituto de Salud Carlos III [“Contrato Post Formación Sanitaria Especializada” FIS CM07/00043] (to G.C.). Centro de Investigación Biomédica en Red-Enfermedades Hepáticas y Digestivas was founded by the Instituto de Salud Carlos III (Spain).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- AP
- apelin
- HSC
- hepatic stellate cell
- APJ
- apelin receptor
- AM1241
- (R,S)-3-(2-iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole
- F13A
- [Ala13]-apelin-13 sequence: Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Ala
- MAP
- mean arterial pressure
- PP
- portal pressure
- SPP
- splanchnic perfusion pressure
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick-end labeling
- PDGFRβ
- platelet-derived growth factor receptor β
- TGFβR1
- transforming growth factor β receptor 1
- Col1α2
- collagen-Iα2
- α-SMA
- α-smooth muscle actin
- TIMP
- tissue inhibitor of matrix metalloproteinase
- MMP
- matrix metalloproteinase
- HPRT
- hypoxanthine guanine phosphoribosyltransferase
- vWF
- von Willebrand factor
- AST
- aspartate aminotransferase
- ALT
- alanine aminotransferase
- ANOVA
- analysis of variance
- ECM
- extracellular matrix
- PDGF
- platelet-derived growth factor
- Col1
- collagen type 1
- CT
- comparative threshold cycle.
- Received September 15, 2011.
- Accepted December 6, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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