title: Matrix conditions and KLF2-dependent induction of heme oxygenase-1 modulate inhibition of HCV replication by fluvastatin.
abstract: OBJECTIVE
  HMG-CoA-reductase-inhibitors (statins) have been shown to interfere with HCV replication in vitro. We investigated the mechanism, requirements and contribution of heme oxygenase-1(HO-1)-induction by statins to interference with HCV replication.
  
  
  METHODS
  HO-1-induction by fluva-, simva-, rosuva-, atorva- or pravastatin was correlated to HCV replication, using non-infectious replicon systems as well as the infectious cell culture system. The mechanism of HO-1-induction by statins as well as its relevance for interference with HCV replication was investigated using transient or permanent knockdown cell lines. Polyacrylamide(PAA) gels of different density degrees or the Rho-kinase-inhibitor Hydroxyfasudil were used in order to mimic matrix conditions corresponding to normal versus fibrotic liver tissue.
  
  
  RESULTS
  All statins used, except pravastatin, decreased HCV replication and induced HO-1 expression, as well as interferon response in vitro. HO-1-induction was mediated by reduction of Bach1 expression and induction of the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) cofactor Krueppel-like factor 2 (KLF2). Knockdown of KLF2 or HO-1 abrogated effects of statins on HCV replication. HO-1-induction and anti-viral effects of statins were more pronounced under cell culture conditions mimicking advanced stages of liver disease.
  
  
  CONCLUSIONS
  Statin-mediated effects on HCV replication seem to require HO-1-induction, which is more pronounced in a microenvironment resembling fibrotic liver tissue. This implicates that certain statins might be especially useful to support HCV therapy of patients at advanced stages of liver disease.
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wuestenberg
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Kah
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz Zentrum Munich, Munich, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Singethan
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Sirma
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Amelie Dorothea
authors.initials: AD
authors.lastname: Keller
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sergio René Perez
authors.initials: SR
authors.lastname: Rosal
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Schrader
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Loscher
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tassilo
authors.initials: T
authors.lastname: Volz
authors.affiliation: Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.affiliation: Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Lohmann
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz Zentrum Munich, Munich, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Protzer
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Maura
authors.initials: M
authors.lastname: Dandri
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Gisa
authors.initials: G
authors.lastname: Tiegs
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Sass
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects*; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D012093:Replicon / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000077340:Fluvastatin; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1