title: The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins.
abstract: OBJECTIVE
  Statins improve hepatic endothelial function and liver fibrosis in experimental models of cirrhosis, thus they have been proposed as therapeutic options to ameliorate portal hypertension syndrome. The transcription factor Kruppel-like factor 2 (KLF2) may be induced by statins in liver sinusoidal endothelial cells (SEC), orchestrating an efficient vasoprotective response. The present study aimed at characterizing whether KLF2 mediates statins-derived hepatic protection.
  
  
  METHODS
  Expression of KLF2 and its vasoprotective target genes was determined in SEC freshly isolated from control or CCl(4)-cirrhotic rats treated with four different statins (atorvastatin, mevastatin, simvastatin, and lovastatin), in the presence of mevalonate (or vehicle), under static or controlled shear stress conditions. KLF2-derived vasoprotective transcriptional programs were analyzed in SEC transfected with siRNA for KLF2 or siRNA-control, and incubated with simvastatin. Paracrine effects of SEC highly-expressing KLF2 on the activation status of rat and human hepatic stellate cells (HSC) were evaluated.
  
  
  RESULTS
  Statins administration to SEC induced significant upregulation of KLF2 expression. KLF2 upregulation was observed after 6h of treatment and was accompanied by induction of its vasoprotective programs. Simvastatin vasoprotection was inhibited in the presence of mevalonate, and was magnified in cells cultured under physiological shear stress conditions. Statin-dependent induction of vasoprotective genes was not observed when KLF2 expression was muted with siRNA. SEC overexpressing KLF2 induced quiescence of HSC through a KLF2-nitric oxide-guanylate cyclase-mediated paracrine mechanism.
  
  
  CONCLUSIONS
  Upregulation of hepatic endothelial KLF2-derived transcriptional programs by statins confers vasoprotection and stellate cells deactivation, reinforcing the therapeutic potential of these drugs for liver diseases that course with endothelial dysfunction.
authors.affiliation: Hepatic Hemodynamic Laboratory, August Pi i Sunyer Institute for Biomedical Research (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Barcelona, Spain.
authors.forename: Giusi
authors.initials: G
authors.lastname: Marrone
authors.forename: Lucia
authors.initials: L
authors.lastname: Russo
authors.forename: Eugenio
authors.initials: E
authors.lastname: Rosado
authors.forename: Diana
authors.initials: D
authors.lastname: Hide
authors.forename: Guillermo
authors.initials: G
authors.lastname: García-Cardeña
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: García-Pagán
authors.forename: Jaime
authors.initials: J
authors.lastname: Bosch
authors.forename: Jorge
authors.initials: J
authors.lastname: Gracia-Sancho
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006975:Hypertension, Portal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology; D013314:Stress, Mechanical
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C543921:Klf2 protein, rat; D051741:Kruppel-Like Transcription Factors; D011758:Pyrroles; C012258:mevastatin; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin