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.
Highlights
Liver injuries are usually followed by fibrogenesis and cirrhosis
All three series of experiments consistently demonstrated that Matrix metalloproteinases (MMPs)-9 suppression alleviated portal hypertension
MMP-9 gene deletion effectively ameliorated portal hypertension in bile duct ligation (BDL) mice. These results suggest that MMP-9 inhibition is a reasonable method to control portal hypertension
Summary
Liver injuries are usually followed by fibrogenesis and cirrhosis. Intrahepatic resistance is elevated in liver cirrhosis due to collagen fiber deposition and enhanced intrahepatic vasoconstriction.[1]. MMP-9 activates transforming growth factor (TGF-β), a cytokine that enhances fibrogenesis,[9] and it is upregulated in liver fibrosis.[10] In bile duct ligation (BDL) mice, general inhibitors of MMPs have been shown to attenuate hepatic fibrosis.[11] MMP-9- deficient mice have been reported to exhibit moderate protection against early fibrosis and proteolytic inactive MMP-9 mutants, acting as TIMP-1 antagonists in vitro and inhibiting CCl4-induced liver fibrosis in mice.[12,13] investigations focused on portal hypertension-related derangements are lacking. Considering the remarkable influences of MMP-9 on angiogenesis and fibrogenesis, we hypothesized that MMP-9 inhibition or deletion may attenuate portal hypertension and the associated derangements To test this hypothesis, we firstly investigated the effects of minocycline, a nonselective MMP inhibitor, because of its well-established safety profile. We focused on MMP-2 and MMP-9 inhibition based on the literature review of potentially treatable targets,[9,10,12,13] and confirmed the results with MMP-9 knockout mice
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call