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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Prevention of Fibrosis Progression in CCl4-Treated Rats: Role of the Hepatic Endocannabinoid and Apelin Systems

Vedrana Reichenbach, Josefa Ros, Guillermo Fernández-Varo, Gregori Casals, Pedro Melgar-Lesmes, Teresa Campos, Alexandros Makriyannis, Manuel Morales-Ruiz and Wladimiro Jiménez
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 629-637; DOI: https://doi.org/10.1124/jpet.111.188078
Vedrana Reichenbach
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Josefa Ros
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Guillermo Fernández-Varo
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Gregori Casals
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Pedro Melgar-Lesmes
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Teresa Campos
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Alexandros Makriyannis
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Manuel Morales-Ruiz
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Wladimiro Jiménez
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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.

    http://dx.doi.org/10.1124/jpet.111.188078.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Fibrosis Progression Prevention in CCl4-Treated Rats

Vedrana Reichenbach, Josefa Ros, Guillermo Fernández-Varo, Gregori Casals, Pedro Melgar-Lesmes, Teresa Campos, Alexandros Makriyannis, Manuel Morales-Ruiz and Wladimiro Jiménez
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 629-637; DOI: https://doi.org/10.1124/jpet.111.188078

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Fibrosis Progression Prevention in CCl4-Treated Rats

Vedrana Reichenbach, Josefa Ros, Guillermo Fernández-Varo, Gregori Casals, Pedro Melgar-Lesmes, Teresa Campos, Alexandros Makriyannis, Manuel Morales-Ruiz and Wladimiro Jiménez
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 629-637; DOI: https://doi.org/10.1124/jpet.111.188078
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