title: Protection and reversal of hepatic fibrosis by red wine polyphenols in hyperhomocysteinemic mice.
abstract: Hyperhomocysteinemia leads to several clinical manifestations and, particularly, liver disease. Lowering homocysteine through nutrition or other means might offer preventive or therapeutic benefits. Polyphenols are natural compounds known for their antioxidant and healing properties for vessels. In a previous study we have shown a beneficial effect of a red wine polyphenolic extract (PE) administration on plasma homocysteine level in cystathionine beta synthase deficient mice, a murine model of hyperhomocysteinemia. These mice also develop hepatic fibrosis. As increased matrix metalloproteinase (MMP) 2 has been shown to be involved in the development of hepatic fibrosis, we then focused on the effect of PE administration on expression and activity of MMP-2 in liver of hyperhomocysteinemic mice and its impact on hepatic fibrosis development. PE was added for four weeks to the drinking water of heterozygous cystathionine beta synthase-deficient mice fed a high-methionine diet. Effects of PE administration were examined by histological analysis with Sirius red staining, zymography, immunobloting, real-time quantitative reverse transcriptase polymerase chain reaction, peroxynitrite level, catalase activity and nicotinamide adenine dinucleotide phosphate oxidase activity. We show that administration of PE had a beneficial effect (i) on MMP-2 expression via modulation of nitrotyrosine-modified total protein level and (ii) on MMP-2 activity via modulation of its activator/inhibitor balance. We also demonstrated a reversal effect of PE supplementation on hepatic fibrosis development. Our results demonstrate a preventive action of PE administration on biomarkers of hepatic dysfunction due to hyperhomocysteinemia.
authors.affiliation: Unit of Functional and Adaptive Biology (BFA), Université Paris Diderot-CNRS EAC 4413, Case 7104, 75205 Paris Cedex 13, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Noll
authors.forename: Lamia
authors.initials: L
authors.lastname: Raaf
authors.forename: Chris
authors.initials: C
authors.lastname: Planque
authors.forename: Ludovic
authors.initials: L
authors.lastname: Benard
authors.forename: Lise
authors.initials: L
authors.lastname: Secardin
authors.forename: Emile
authors.initials: E
authors.lastname: Petit
authors.forename: Julien
authors.initials: J
authors.lastname: Dairou
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Paul
authors.forename: Jane-Lise
authors.initials: JL
authors.lastname: Samuel
authors.forename: Claude
authors.initials: C
authors.lastname: Delcayre
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrigues-Lima
authors.forename: Nathalie
authors.initials: N
authors.lastname: Janel
mesh_terms: D000818:Animals; D003541:Cystathionine beta-Synthase / Q000235:genetics; D020138:Hyperhomocysteinemia / Q000150:complications / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008715:Methionine / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D059808:Polyphenols / Q000494:pharmacology* / Q000627:therapeutic use; D014920:Wine
chemical_list: D059808:Polyphenols; D008715:Methionine; D020778:Matrix Metalloproteinase 2; D003541:Cystathionine beta-Synthase