Statins Activate the Canonical Hedgehog-Signaling and Aggravate Non-Cirrhotic Portal Hypertension, but Inhibit the Non-Canonical Hedgehog Signaling and Cirrhotic Portal Hypertension

Sci Rep. 2015 Sep 28;5:14573. doi: 10.1038/srep14573.

Abstract

Liver cirrhosis but also portal vein obstruction cause portal hypertension (PHT) and angiogenesis. This study investigated the differences of angiogenesis in cirrhotic and non-cirrhotic PHT with special emphasis on the canonical (Shh/Gli) and non-canonical (Shh/RhoA) hedgehog pathway. Cirrhotic (bile duct ligation/BDL; CCl4 intoxication) and non-cirrhotic (partial portal vein ligation/PPVL) rats received either atorvastatin (15 mg/kg; 7d) or control chow before sacrifice. Invasive hemodynamic measurement and Matrigel implantation assessed angiogenesis in vivo. Angiogenesis in vitro was analysed using migration and tube formation assay. In liver and vessel samples from animals and humans, transcript expression was analyzed using RT-PCR and protein expression using Western blot. Atorvastatin decreased portal pressure, shunt flow and angiogenesis in cirrhosis, whereas atorvastatin increased these parameters in PPVL rats. Non-canonical Hh was upregulated in experimental and human liver cirrhosis and was blunted by atorvastatin. Moreover, atorvastatin blocked the non-canonical Hh-pathway RhoA dependently in activated hepatic steallate cells (HSCs). Interestingly, hepatic and extrahepatic Hh-pathway was enhanced in PPVL rats, which resulted in increased angiogenesis. In summary, statins caused contrary effects in cirrhotic and non-cirrhotic portal hypertension. Atorvastatin inhibited the non-canonical Hh-pathway and angiogenesis in cirrhosis. In portal vein obstruction, statins enhanced the canonical Hh-pathway and aggravated PHT and angiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Cell Line
  • Disease Models, Animal
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Hemodynamics / drug effects
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / metabolism
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Hypertension, Portal / drug therapy
  • Hypertension, Portal / etiology*
  • Hypertension, Portal / metabolism*
  • Hypertension, Portal / physiopathology
  • Liver Cirrhosis / complications
  • Liver Cirrhosis / metabolism
  • Models, Biological
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Rats
  • Signal Transduction / drug effects*
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Biomarkers
  • Hedgehog Proteins
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • rhoA GTP-Binding Protein