title: KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins.
abstract: OBJECTIVE
  In the liver, the transcription factor, Kruppel-like factor 2 (KLF2), is induced early during progression of cirrhosis to lessen the development of vascular dysfunction; nevertheless, its endogenous expression results insufficient to attenuate establishment of portal hypertension and aggravation of cirrhosis. Herein, we aimed to explore the effects and the underlying mechanisms of hepatic KLF2 overexpression in in vitro and in vivo models of liver cirrhosis.
  
  
  METHODS
  Activation phenotype was evaluated in human and rat cirrhotic hepatic stellate cells (HSC) treated with the pharmacological inductor of KLF2 simvastatin, with adenovirus codifying for this transcription factor (Ad-KLF2), or vehicle, in presence/absence of inhibitors of KLF2. Possible paracrine interactions between parenchymal and non-parenchymal cells overexpressing KLF2 were studied. Effects of in vivo hepatic KLF2 overexpression on liver fibrosis and systemic and hepatic haemodynamics were assessed in cirrhotic rats.
  
  
  RESULTS
  KLF2 upregulation profoundly ameliorated HSC phenotype (reduced α-smooth muscle actin, procollagen I and oxidative stress) partly via the activation of the nuclear factor (NF)-E2-related factor 2 (Nrf2). Coculture experiments showed that improvement in HSC phenotype paracrinally ameliorated liver sinusoidal endothelial cells probably through a vascular endothelial growth factor-mediated mechanism. No paracrine interactions between hepatocytes and HSC were observed. Cirrhotic rats treated with simvastatin or Ad-KLF2 showed hepatic upregulation in the KLF2-Nrf2 pathway, deactivation of HSC and prominent reduction in liver fibrosis. Hepatic KLF2 overexpression was associated with lower portal pressure (-15%) due to both attenuations in the increased portal blood flow and hepatic vascular resistance, together with a significant improvement in hepatic endothelial dysfunction.
  
  
  CONCLUSIONS
  Exogenous hepatic KLF2 upregulation improves liver fibrosis, endothelial dysfunction and portal hypertension in cirrhosis.
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
authors.forename: Giusi
authors.initials: G
authors.lastname: Marrone
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Maeso-Díaz
authors.affiliation: Departments of Pathology, Brigham and Women's Hospital & Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: García-Cardena
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
authors.forename: Juan G
authors.initials: JG
authors.lastname: Abraldes
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: García-Pagán
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Bosch
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
authors.forename: Jordi
authors.identifier: http://orcid.org/0000-0001-7736-4089
authors.initials: J
authors.lastname: Gracia-Sancho
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods; D010641:Phenotype; D020011:Protective Agents / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D019821:Simvastatin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000933:Antifibrinolytic Agents; C543921:Klf2 protein, rat; D051741:Kruppel-Like Transcription Factors; D020011:Protective Agents; D019821:Simvastatin
keywords: PORTAL HYPERTENSION