Protection and reversal of hepatic fibrosis by red wine polyphenols in hyperhomocysteinemic mice

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.