Transcriptional regulation of Nox4 by histone deacetylases in human endothelial cells
Nox4 is a member of the NADPH oxidase family, which represents a major source of reactive oxygen species (ROS) in the vascular wall. Nox4-mediated ROS production mainly depends on the expression levels of the enzyme. The present study was aimed to investigate the mechanisms of Nox4 transcription reg...
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| Veröffentlicht in: | Basic research in cardiology 2012-09, Vol.107 (5), p.283-283, Article 283 |
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| creator | Siuda, Daniel Zechner, Ulrich El Hajj, Nady Prawitt, Dirk Langer, David Xia, Ning Horke, Sven Pautz, Andrea Kleinert, Hartmut Förstermann, Ulrich Li, Huige |
| description | Nox4 is a member of the NADPH oxidase family, which represents a major source of reactive oxygen species (ROS) in the vascular wall. Nox4-mediated ROS production mainly depends on the expression levels of the enzyme. The present study was aimed to investigate the mechanisms of Nox4 transcription regulation by histone deacetylases (HDAC). In human umbilical vein endothelial cells (HUVEC) and HUVEC-derived EA.hy 926 cells, treatment with the pan-HDAC inhibitor scriptaid led to a marked decrease in Nox4 mRNA expression. A similar down-regulation of Nox4 mRNA expression was observed by siRNA-mediated knockdown of HDAC3. HDAC inhibition in endothelial cells was associated with enhanced histone acetylation, increased chromatin accessibility in the human Nox4 promoter region, with no significant changes in DNA methylation. In addition, we provided evidence that c-Jun played an important role in controlling Nox4 transcription. Knockdown of c-Jun with siRNA led to a down-regulation of Nox4 mRNA expression. In response to scriptaid treatment, the binding of c-Jun to the Nox4 promoter region was reduced despite the open chromatin structure. In parallel, the binding of RNA polymerase IIa to the Nox4 promoter was significantly inhibited as well, which may explain the reduction in Nox4 transcription. In conclusion, HDAC inhibition decreases Nox4 transcription in human endothelial cells by preventing the binding of transcription factor(s) and polymerase(s) to the Nox4 promoter, most likely because of a hyperacetylation-mediated steric inhibition. |
| doi_str_mv | 10.1007/s00395-012-0283-3 |
| format | Article |
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Nox4-mediated ROS production mainly depends on the expression levels of the enzyme. The present study was aimed to investigate the mechanisms of Nox4 transcription regulation by histone deacetylases (HDAC). In human umbilical vein endothelial cells (HUVEC) and HUVEC-derived EA.hy 926 cells, treatment with the pan-HDAC inhibitor scriptaid led to a marked decrease in Nox4 mRNA expression. A similar down-regulation of Nox4 mRNA expression was observed by siRNA-mediated knockdown of HDAC3. HDAC inhibition in endothelial cells was associated with enhanced histone acetylation, increased chromatin accessibility in the human Nox4 promoter region, with no significant changes in DNA methylation. In addition, we provided evidence that c-Jun played an important role in controlling Nox4 transcription. Knockdown of c-Jun with siRNA led to a down-regulation of Nox4 mRNA expression. In response to scriptaid treatment, the binding of c-Jun to the Nox4 promoter region was reduced despite the open chromatin structure. In parallel, the binding of RNA polymerase IIa to the Nox4 promoter was significantly inhibited as well, which may explain the reduction in Nox4 transcription. In conclusion, HDAC inhibition decreases Nox4 transcription in human endothelial cells by preventing the binding of transcription factor(s) and polymerase(s) to the Nox4 promoter, most likely because of a hyperacetylation-mediated steric inhibition.</description><identifier>ISSN: 0300-8428</identifier><identifier>EISSN: 1435-1803</identifier><identifier>DOI: 10.1007/s00395-012-0283-3</identifier><identifier>PMID: 22791246</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>Acetylation ; Base Sequence ; c-Jun protein ; Cardiology ; Cells, Cultured ; Chromatin ; DNA Methylation ; DNA-directed RNA polymerase ; Endothelial cells ; Endothelial Cells - drug effects ; Endothelial Cells - enzymology ; Enzymes ; Gene expression ; Gene Expression Regulation ; Gene regulation ; Histone deacetylase ; Histone Deacetylase Inhibitors - pharmacology ; Histone Deacetylases - physiology ; Histones - metabolism ; Humans ; Medicine ; Medicine & Public Health ; Molecular Sequence Data ; NAD(P)H oxidase ; NADPH Oxidase 4 ; NADPH Oxidases - genetics ; NOX4 protein ; Original Contribution ; Promoter Regions, Genetic ; Promoters ; Proto-Oncogene Proteins c-jun - physiology ; Reactive oxygen species ; siRNA ; Transcription factors ; Transcription, Genetic ; umbilical vein</subject><ispartof>Basic research in cardiology, 2012-09, Vol.107 (5), p.283-283, Article 283</ispartof><rights>Springer-Verlag 2012</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c405t-6fedd53db1ef28cc5c56c5815df60004df2243101cc21ae08c70e90699f776bf3</citedby><cites>FETCH-LOGICAL-c405t-6fedd53db1ef28cc5c56c5815df60004df2243101cc21ae08c70e90699f776bf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00395-012-0283-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00395-012-0283-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22791246$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Siuda, Daniel</creatorcontrib><creatorcontrib>Zechner, Ulrich</creatorcontrib><creatorcontrib>El Hajj, Nady</creatorcontrib><creatorcontrib>Prawitt, Dirk</creatorcontrib><creatorcontrib>Langer, David</creatorcontrib><creatorcontrib>Xia, Ning</creatorcontrib><creatorcontrib>Horke, Sven</creatorcontrib><creatorcontrib>Pautz, Andrea</creatorcontrib><creatorcontrib>Kleinert, Hartmut</creatorcontrib><creatorcontrib>Förstermann, Ulrich</creatorcontrib><creatorcontrib>Li, Huige</creatorcontrib><title>Transcriptional regulation of Nox4 by histone deacetylases in human endothelial cells</title><title>Basic research in cardiology</title><addtitle>Basic Res Cardiol</addtitle><addtitle>Basic Res Cardiol</addtitle><description>Nox4 is a member of the NADPH oxidase family, which represents a major source of reactive oxygen species (ROS) in the vascular wall. Nox4-mediated ROS production mainly depends on the expression levels of the enzyme. The present study was aimed to investigate the mechanisms of Nox4 transcription regulation by histone deacetylases (HDAC). In human umbilical vein endothelial cells (HUVEC) and HUVEC-derived EA.hy 926 cells, treatment with the pan-HDAC inhibitor scriptaid led to a marked decrease in Nox4 mRNA expression. A similar down-regulation of Nox4 mRNA expression was observed by siRNA-mediated knockdown of HDAC3. HDAC inhibition in endothelial cells was associated with enhanced histone acetylation, increased chromatin accessibility in the human Nox4 promoter region, with no significant changes in DNA methylation. In addition, we provided evidence that c-Jun played an important role in controlling Nox4 transcription. Knockdown of c-Jun with siRNA led to a down-regulation of Nox4 mRNA expression. In response to scriptaid treatment, the binding of c-Jun to the Nox4 promoter region was reduced despite the open chromatin structure. In parallel, the binding of RNA polymerase IIa to the Nox4 promoter was significantly inhibited as well, which may explain the reduction in Nox4 transcription. In conclusion, HDAC inhibition decreases Nox4 transcription in human endothelial cells by preventing the binding of transcription factor(s) and polymerase(s) to the Nox4 promoter, most likely because of a hyperacetylation-mediated steric inhibition.</description><subject>Acetylation</subject><subject>Base Sequence</subject><subject>c-Jun protein</subject><subject>Cardiology</subject><subject>Cells, Cultured</subject><subject>Chromatin</subject><subject>DNA Methylation</subject><subject>DNA-directed RNA polymerase</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - enzymology</subject><subject>Enzymes</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Gene regulation</subject><subject>Histone deacetylase</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Histone Deacetylases - physiology</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Molecular Sequence Data</subject><subject>NAD(P)H oxidase</subject><subject>NADPH Oxidase 4</subject><subject>NADPH Oxidases - genetics</subject><subject>NOX4 protein</subject><subject>Original Contribution</subject><subject>Promoter Regions, Genetic</subject><subject>Promoters</subject><subject>Proto-Oncogene Proteins c-jun - physiology</subject><subject>Reactive oxygen species</subject><subject>siRNA</subject><subject>Transcription factors</subject><subject>Transcription, Genetic</subject><subject>umbilical vein</subject><issn>0300-8428</issn><issn>1435-1803</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFkcFq3DAQhkVpSLZJHqCXIuglFyczkmxJxxLatBCSS3I2WnmUdfBaW8mG7ttHZtNSCiUnMej7_xH6GPuIcIkA-ioDSFtXgKICYWQl37EVKllXaEC-ZyuQAJVRwpywDzk_A6BqGjxmJ0Joi0I1K_b4kNyYfep3Ux9HN_BET_PgloHHwO_iL8XXe77p8xRH4h05T9N-cJky70e-mbdu5DR2cdrQ0Je8p2HIZ-wouCHT-et5yh6_fX24_l7d3t_8uP5yW3kF9VQ1gbqult0aKQjjfe3rxtcG6y40AKC6IISSCOi9QEdgvAay0FgbtG7WQZ6yi0PvLsWfM-Wp3fZ5eYEbKc65RdRojAaJb6MglJVaS1HQz_-gz3FO5XMWSlopjLa2UHigfIo5JwrtLvVbl_YFahc97UFPW_S0i55Wlsyn1-Z5vaXuT-K3jwKIA5DL1fhE6e_V_2t9Aeyumac</recordid><startdate>20120901</startdate><enddate>20120901</enddate><creator>Siuda, Daniel</creator><creator>Zechner, Ulrich</creator><creator>El Hajj, Nady</creator><creator>Prawitt, Dirk</creator><creator>Langer, David</creator><creator>Xia, Ning</creator><creator>Horke, Sven</creator><creator>Pautz, Andrea</creator><creator>Kleinert, Hartmut</creator><creator>Förstermann, Ulrich</creator><creator>Li, Huige</creator><general>Springer-Verlag</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M7Z</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>7TM</scope></search><sort><creationdate>20120901</creationdate><title>Transcriptional regulation of Nox4 by histone deacetylases in human endothelial cells</title><author>Siuda, Daniel ; Zechner, Ulrich ; El Hajj, Nady ; Prawitt, Dirk ; Langer, David ; Xia, Ning ; Horke, Sven ; Pautz, Andrea ; Kleinert, Hartmut ; Förstermann, Ulrich ; Li, Huige</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c405t-6fedd53db1ef28cc5c56c5815df60004df2243101cc21ae08c70e90699f776bf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Acetylation</topic><topic>Base Sequence</topic><topic>c-Jun protein</topic><topic>Cardiology</topic><topic>Cells, Cultured</topic><topic>Chromatin</topic><topic>DNA Methylation</topic><topic>DNA-directed RNA polymerase</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - enzymology</topic><topic>Enzymes</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Gene regulation</topic><topic>Histone deacetylase</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Histone Deacetylases - physiology</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Molecular Sequence Data</topic><topic>NAD(P)H oxidase</topic><topic>NADPH Oxidase 4</topic><topic>NADPH Oxidases - genetics</topic><topic>NOX4 protein</topic><topic>Original Contribution</topic><topic>Promoter Regions, Genetic</topic><topic>Promoters</topic><topic>Proto-Oncogene Proteins c-jun - physiology</topic><topic>Reactive oxygen species</topic><topic>siRNA</topic><topic>Transcription factors</topic><topic>Transcription, Genetic</topic><topic>umbilical vein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Siuda, Daniel</creatorcontrib><creatorcontrib>Zechner, Ulrich</creatorcontrib><creatorcontrib>El Hajj, Nady</creatorcontrib><creatorcontrib>Prawitt, Dirk</creatorcontrib><creatorcontrib>Langer, David</creatorcontrib><creatorcontrib>Xia, Ning</creatorcontrib><creatorcontrib>Horke, Sven</creatorcontrib><creatorcontrib>Pautz, Andrea</creatorcontrib><creatorcontrib>Kleinert, Hartmut</creatorcontrib><creatorcontrib>Förstermann, Ulrich</creatorcontrib><creatorcontrib>Li, Huige</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biochemistry Abstracts 1</collection><collection>Biotechnology and BioEngineering Abstracts</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>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><jtitle>Basic research in cardiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Siuda, Daniel</au><au>Zechner, Ulrich</au><au>El Hajj, Nady</au><au>Prawitt, Dirk</au><au>Langer, David</au><au>Xia, Ning</au><au>Horke, Sven</au><au>Pautz, Andrea</au><au>Kleinert, Hartmut</au><au>Förstermann, Ulrich</au><au>Li, Huige</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transcriptional regulation of Nox4 by histone deacetylases in human endothelial cells</atitle><jtitle>Basic research in cardiology</jtitle><stitle>Basic Res Cardiol</stitle><addtitle>Basic Res Cardiol</addtitle><date>2012-09-01</date><risdate>2012</risdate><volume>107</volume><issue>5</issue><spage>283</spage><epage>283</epage><pages>283-283</pages><artnum>283</artnum><issn>0300-8428</issn><eissn>1435-1803</eissn><abstract>Nox4 is a member of the NADPH oxidase family, which represents a major source of reactive oxygen species (ROS) in the vascular wall. Nox4-mediated ROS production mainly depends on the expression levels of the enzyme. The present study was aimed to investigate the mechanisms of Nox4 transcription regulation by histone deacetylases (HDAC). In human umbilical vein endothelial cells (HUVEC) and HUVEC-derived EA.hy 926 cells, treatment with the pan-HDAC inhibitor scriptaid led to a marked decrease in Nox4 mRNA expression. A similar down-regulation of Nox4 mRNA expression was observed by siRNA-mediated knockdown of HDAC3. HDAC inhibition in endothelial cells was associated with enhanced histone acetylation, increased chromatin accessibility in the human Nox4 promoter region, with no significant changes in DNA methylation. In addition, we provided evidence that c-Jun played an important role in controlling Nox4 transcription. Knockdown of c-Jun with siRNA led to a down-regulation of Nox4 mRNA expression. In response to scriptaid treatment, the binding of c-Jun to the Nox4 promoter region was reduced despite the open chromatin structure. In parallel, the binding of RNA polymerase IIa to the Nox4 promoter was significantly inhibited as well, which may explain the reduction in Nox4 transcription. In conclusion, HDAC inhibition decreases Nox4 transcription in human endothelial cells by preventing the binding of transcription factor(s) and polymerase(s) to the Nox4 promoter, most likely because of a hyperacetylation-mediated steric inhibition.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>22791246</pmid><doi>10.1007/s00395-012-0283-3</doi><tpages>1</tpages></addata></record> |
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| subjects | Acetylation Base Sequence c-Jun protein Cardiology Cells, Cultured Chromatin DNA Methylation DNA-directed RNA polymerase Endothelial cells Endothelial Cells - drug effects Endothelial Cells - enzymology Enzymes Gene expression Gene Expression Regulation Gene regulation Histone deacetylase Histone Deacetylase Inhibitors - pharmacology Histone Deacetylases - physiology Histones - metabolism Humans Medicine Medicine & Public Health Molecular Sequence Data NAD(P)H oxidase NADPH Oxidase 4 NADPH Oxidases - genetics NOX4 protein Original Contribution Promoter Regions, Genetic Promoters Proto-Oncogene Proteins c-jun - physiology Reactive oxygen species siRNA Transcription factors Transcription, Genetic umbilical vein |
| title | Transcriptional regulation of Nox4 by histone deacetylases in human endothelial cells |
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