Matrix metalloproteinase-9 inhibition or deletion attenuates portal hypertension in rodents

Abstract

Liver cirrhosis and portal hypertension are accompanied by hyperdynamic circulation, angiogenesis and portosystemic collaterals. Matrix metalloproteinases (MMPs) participate in fibrogenesis and angiogenesis, however, whether they can be targeted in cirrhosis treatment is unclear. Therefore, we performed three series of experiments to investigate this issue. Liver cirrhosis was induced by common bile duct ligation (BDL) in Sprague-Dawley rats. Sham-operated rats served as controls. Rats were randomly allocated to receive vehicle, minocycline (a nonselective MMP inhibitor) or SB-3CT (MMP-2 and -9 inhibitor) for 28 days in the first and second series, respectively. MMP-9 knockout mice were used in the third series. The results showed that minocycline ameliorated portal hypertension, hemodynamic abnormalities, reduced collateral shunting, mesenteric vascular density, plasma VEGF level and alleviated liver fibrosis. SB-3CT attenuated portal hypertension, hemodynamic derangements, reduced shunting, mesenteric vascular density, mesenteric VEGF protein expression, and liver fibrosis. Knockout BDL mice had significantly alleviated portal hypertension, liver fibrosis, liver α-SMA and mesenteric eNOS protein expressions compared to wild-type BDL mice. Liver SMAD2 phosphorylation was down-regulated in all series with MMP inhibition or knock-out. In conclusion, MMP-9 inhibition or deletion ameliorated the severity of cirrhosis, portal hypertension, and associated derangements. MMP-9 may be targeted in the treatment of liver cirrhosis.

Keywords: angiogenesis; liver cirrhosis; metalloproteinase; portal hypertension; portosystemic collaterals.