title: Statins activate the canonical hedgehog-signaling and aggravate non-cirrhotic portal hypertension, but inhibit the non-canonical hedgehog signaling and cirrhotic portal hypertension.
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.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany.
authors.forename: Frank E
authors.initials: FE
authors.lastname: Uschner
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Ranabhat
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Steve S
authors.initials: SS
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Granzow
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Schierwagen
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Raskopf
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Gautsch
authors.affiliation: Institute for Cell Biology, University of Bonn, Germany.
authors.forename: Peter F M
authors.initials: PF
authors.lastname: van der Ven
authors.affiliation: Institute for Cell Biology, University of Bonn, Germany.
authors.forename: Dieter O
authors.initials: DO
authors.lastname: Fürst
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Strassburg
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany.
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
mesh_terms: D000818:Animals; D015415:Biomarkers; D002460:Cell Line; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006975:Hypertension, Portal / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D015415:Biomarkers; D053823:Hedgehog Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020742:rhoA GTP-Binding Protein