Matrix conditions and KLF2-dependent induction of heme oxygenase-1 modulate inhibition of HCV replication by fluvastatin
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. HO-1-induction by fluva-, simva-, rosuva-, atorva- or p...
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| Veröffentlicht in: | PloS one 2014-05, Vol.9 (5), p.e96533 |
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| creator | Wuestenberg, Andrea Kah, Janine Singethan, Katrin Sirma, Hüseyin Keller, Amelie Dorothea Rosal, Sergio René Perez Schrader, Jörg Loscher, Christine Volz, Tassilo Bartenschlager, Ralf Lohmann, Volker Protzer, Ulrike Dandri, Maura Lohse, Ansgar W Tiegs, Gisa Sass, Gabriele |
| description | 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.
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.
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.
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. |
| doi_str_mv | 10.1371/journal.pone.0096533 |
| format | Article |
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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.
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.
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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0096533</identifier><identifier>PMID: 24801208</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Antilipemic agents ; Antiviral agents ; Antiviral Agents - pharmacology ; Basic-Leucine Zipper Transcription Factors - metabolism ; Biological response modifiers ; Biology and Life Sciences ; Biosynthesis ; Cancer ; Cell culture ; Cell Line ; Cell lines ; Cholesterol ; DNA Replication - drug effects ; Enzyme inhibitors ; Enzymes ; Fanconi Anemia Complementation Group Proteins - metabolism ; Fatty Acids, Monounsaturated - pharmacology ; Fibrosis ; Fluvastatin ; Gels ; Heme ; Heme oxygenase (decyclizing) ; Heme Oxygenase-1 - metabolism ; Hepacivirus - drug effects ; Hepatitis ; Hepatitis C virus ; Hepatology ; Humans ; Immunology ; Indoles - pharmacology ; Infections ; Infectious diseases ; Interference ; Interferon ; Krueppel-like factor ; Kruppel-Like Transcription Factors - metabolism ; Liver ; Liver diseases ; Medicine ; Medicine and health sciences ; Mimicry ; NF-E2-Related Factor 2 - metabolism ; Oxygenase ; Pravastatin ; Reductase ; Replication ; Replicon - drug effects ; Rho-associated kinase ; Statins ; Viral infections ; Virology ; Virus Replication - drug effects</subject><ispartof>PloS one, 2014-05, Vol.9 (5), p.e96533</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Wuestenberg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Wuestenberg et al 2014 Wuestenberg et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-a3e7de659fd9d542deb3e451aa25873b73346e6300568c01762a9df80d4d69383</citedby><cites>FETCH-LOGICAL-c692t-a3e7de659fd9d542deb3e451aa25873b73346e6300568c01762a9df80d4d69383</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011762/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011762/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24801208$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wuestenberg, Andrea</creatorcontrib><creatorcontrib>Kah, Janine</creatorcontrib><creatorcontrib>Singethan, Katrin</creatorcontrib><creatorcontrib>Sirma, Hüseyin</creatorcontrib><creatorcontrib>Keller, Amelie Dorothea</creatorcontrib><creatorcontrib>Rosal, Sergio René Perez</creatorcontrib><creatorcontrib>Schrader, Jörg</creatorcontrib><creatorcontrib>Loscher, Christine</creatorcontrib><creatorcontrib>Volz, Tassilo</creatorcontrib><creatorcontrib>Bartenschlager, Ralf</creatorcontrib><creatorcontrib>Lohmann, Volker</creatorcontrib><creatorcontrib>Protzer, Ulrike</creatorcontrib><creatorcontrib>Dandri, Maura</creatorcontrib><creatorcontrib>Lohse, Ansgar W</creatorcontrib><creatorcontrib>Tiegs, Gisa</creatorcontrib><creatorcontrib>Sass, Gabriele</creatorcontrib><title>Matrix conditions and KLF2-dependent induction of heme oxygenase-1 modulate inhibition of HCV replication by fluvastatin</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.
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.
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.
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.</description><subject>Antilipemic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - pharmacology</subject><subject>Basic-Leucine Zipper Transcription Factors - metabolism</subject><subject>Biological response modifiers</subject><subject>Biology and Life Sciences</subject><subject>Biosynthesis</subject><subject>Cancer</subject><subject>Cell culture</subject><subject>Cell Line</subject><subject>Cell lines</subject><subject>Cholesterol</subject><subject>DNA Replication - drug effects</subject><subject>Enzyme inhibitors</subject><subject>Enzymes</subject><subject>Fanconi Anemia Complementation Group Proteins - metabolism</subject><subject>Fatty Acids, Monounsaturated - pharmacology</subject><subject>Fibrosis</subject><subject>Fluvastatin</subject><subject>Gels</subject><subject>Heme</subject><subject>Heme oxygenase (decyclizing)</subject><subject>Heme Oxygenase-1 - metabolism</subject><subject>Hepacivirus - drug effects</subject><subject>Hepatitis</subject><subject>Hepatitis C virus</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Immunology</subject><subject>Indoles - pharmacology</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Interference</subject><subject>Interferon</subject><subject>Krueppel-like factor</subject><subject>Kruppel-Like Transcription Factors - metabolism</subject><subject>Liver</subject><subject>Liver diseases</subject><subject>Medicine</subject><subject>Medicine and health sciences</subject><subject>Mimicry</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Oxygenase</subject><subject>Pravastatin</subject><subject>Reductase</subject><subject>Replication</subject><subject>Replicon - drug effects</subject><subject>Rho-associated kinase</subject><subject>Statins</subject><subject>Viral infections</subject><subject>Virology</subject><subject>Virus Replication - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wuestenberg, Andrea</au><au>Kah, Janine</au><au>Singethan, Katrin</au><au>Sirma, Hüseyin</au><au>Keller, Amelie Dorothea</au><au>Rosal, Sergio René Perez</au><au>Schrader, Jörg</au><au>Loscher, Christine</au><au>Volz, Tassilo</au><au>Bartenschlager, Ralf</au><au>Lohmann, Volker</au><au>Protzer, Ulrike</au><au>Dandri, Maura</au><au>Lohse, Ansgar W</au><au>Tiegs, Gisa</au><au>Sass, Gabriele</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Matrix conditions and KLF2-dependent induction of heme oxygenase-1 modulate inhibition of HCV replication by fluvastatin</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-05-06</date><risdate>2014</risdate><volume>9</volume><issue>5</issue><spage>e96533</spage><pages>e96533-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.
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.
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.
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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24801208</pmid><doi>10.1371/journal.pone.0096533</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-05, Vol.9 (5), p.e96533 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1521422679 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Antilipemic agents Antiviral agents Antiviral Agents - pharmacology Basic-Leucine Zipper Transcription Factors - metabolism Biological response modifiers Biology and Life Sciences Biosynthesis Cancer Cell culture Cell Line Cell lines Cholesterol DNA Replication - drug effects Enzyme inhibitors Enzymes Fanconi Anemia Complementation Group Proteins - metabolism Fatty Acids, Monounsaturated - pharmacology Fibrosis Fluvastatin Gels Heme Heme oxygenase (decyclizing) Heme Oxygenase-1 - metabolism Hepacivirus - drug effects Hepatitis Hepatitis C virus Hepatology Humans Immunology Indoles - pharmacology Infections Infectious diseases Interference Interferon Krueppel-like factor Kruppel-Like Transcription Factors - metabolism Liver Liver diseases Medicine Medicine and health sciences Mimicry NF-E2-Related Factor 2 - metabolism Oxygenase Pravastatin Reductase Replication Replicon - drug effects Rho-associated kinase Statins Viral infections Virology Virus Replication - drug effects |
| title | Matrix conditions and KLF2-dependent induction of heme oxygenase-1 modulate inhibition of HCV replication by fluvastatin |
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