title: Prevention of fibrosis progression in CCl4-treated rats: role of the hepatic endocannabinoid and apelin systems.
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 CCl(4)-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 [Ala(13)]-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 CCl(4) 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 CCl(4)-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.
authors.affiliation: Service of Biochemistry and Molecular Genetics, Hospital Clínic, Barcelona, Spain.
authors.forename: Vedrana
authors.initials: V
authors.lastname: Reichenbach
authors.forename: Josefa
authors.initials: J
authors.lastname: Ros
authors.forename: Guillermo
authors.initials: G
authors.lastname: Fernández-Varo
authors.forename: Gregori
authors.initials: G
authors.lastname: Casals
authors.forename: Pedro
authors.initials: P
authors.lastname: Melgar-Lesmes
authors.forename: Teresa
authors.initials: T
authors.lastname: Campos
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.forename: Manuel
authors.initials: M
authors.lastname: Morales-Ruiz
authors.forename: Wladimiro
authors.initials: W
authors.lastname: Jiménez
mesh_terms: D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D017209:Apoptosis; D001794:Blood Pressure; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D002251:Carbon Tetrachloride / Q000633:toxicity; D053148:Caspase 3 / Q000502:physiology; D018450:Disease Progression; D063388:Endocannabinoids; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008106:Liver Cirrhosis, Experimental / Q000517:prevention & control*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2 / Q000502:physiology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000032:analysis; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis
chemical_list: D000073861:Apelin; D000075244:Apelin Receptors; C498579:Apln protein, rat; C491284:Aplnr protein, rat; D063385:Cannabinoid Receptor Modulators; C469526:Cnr2 protein, rat; D063388:Endocannabinoids; D036341:Intercellular Signaling Peptides and Proteins; D043885:Receptor, Cannabinoid, CB2; D043562:Receptors, G-Protein-Coupled; D019715:Tissue Inhibitor of Metalloproteinase-1; D002251:Carbon Tetrachloride; D020797:Receptor, Platelet-Derived Growth Factor beta; D053148:Caspase 3