Native and Oxidized Low Density Lipoprotein Induction of Tissue Factor Gene Expression in Smooth Muscle Cells Is Mediated by Both Egr-1 and Sp1
Tissue factor, in association with factor VIIa, initiates the coagulation cascade. We studied the influences of two pathophysiological stimuli, native (unmodified) and oxidized low density lipoprotein, on tissue factor gene expression in a cell important in vascular remodeling and vascular diseases,...
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| Veröffentlicht in: | The Journal of biological chemistry 1999-11, Vol.274 (46), p.32795-32802 |
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| creator | Cui, Mei-Zhen Penn, Marc S. Chisolm, Guy M. |
| description | Tissue factor, in association with factor VIIa, initiates the coagulation cascade. We studied the influences of two pathophysiological stimuli, native (unmodified) and oxidized low density lipoprotein, on tissue factor gene expression in a cell important in vascular remodeling and vascular diseases, the smooth muscle cell. Our results demonstrated that both lipoproteins significantly induced tissue factor gene expression in rat aortic smooth muscle cells; oxidized low density lipoprotein was slightly more potent. Both lipoproteins increased tissue factor mRNA in a concentration- and time-dependent manner. Results from nuclear run-on assays and mRNA stability experiments indicated that increased tissue factor mRNA accumulation in response to the lipoproteins was principally controlled at the transcriptional level. By using lipid extracts of low density lipoprotein or methylation of the intact lipoprotein to block receptor recognition, we showed that this lipoprotein induced tissue factor mRNA via both receptor-independent and receptor-augmented pathways. Transfection studies using a series of deleted tissue factor promoters revealed that a −143- to +106-base pair region of the rat tissue factor promoter contained regulatory elements required for lipoprotein-mediated induction. Electrophoretic mobility shift assays showed that the binding activities of the transcription factor Egr-1, but not Sp1, were markedly elevated in response to these lipoproteins. Transfection of site-directed mutants of the tissue factor (TF) promoter demonstrated that not only Egr-1 but also Sp1 cis-acting elements in the TF (−143) promoter construct were necessary for optimal TF gene induction. Our data show for the first time that both low density lipoprotein and oxidized low density lipoprotein induce tissue factor gene expression in smooth muscle cells and that this tissue factor gene expression is mediated by both Egr-1 and Sp1 transcription factors. |
| doi_str_mv | 10.1074/jbc.274.46.32795 |
| format | Article |
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We studied the influences of two pathophysiological stimuli, native (unmodified) and oxidized low density lipoprotein, on tissue factor gene expression in a cell important in vascular remodeling and vascular diseases, the smooth muscle cell. Our results demonstrated that both lipoproteins significantly induced tissue factor gene expression in rat aortic smooth muscle cells; oxidized low density lipoprotein was slightly more potent. Both lipoproteins increased tissue factor mRNA in a concentration- and time-dependent manner. Results from nuclear run-on assays and mRNA stability experiments indicated that increased tissue factor mRNA accumulation in response to the lipoproteins was principally controlled at the transcriptional level. By using lipid extracts of low density lipoprotein or methylation of the intact lipoprotein to block receptor recognition, we showed that this lipoprotein induced tissue factor mRNA via both receptor-independent and receptor-augmented pathways. Transfection studies using a series of deleted tissue factor promoters revealed that a −143- to +106-base pair region of the rat tissue factor promoter contained regulatory elements required for lipoprotein-mediated induction. Electrophoretic mobility shift assays showed that the binding activities of the transcription factor Egr-1, but not Sp1, were markedly elevated in response to these lipoproteins. Transfection of site-directed mutants of the tissue factor (TF) promoter demonstrated that not only Egr-1 but also Sp1 cis-acting elements in the TF (−143) promoter construct were necessary for optimal TF gene induction. Our data show for the first time that both low density lipoprotein and oxidized low density lipoprotein induce tissue factor gene expression in smooth muscle cells and that this tissue factor gene expression is mediated by both Egr-1 and Sp1 transcription factors.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.274.46.32795</identifier><identifier>PMID: 10551840</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; aorta ; Base Sequence ; binding ; blood coagulation factors ; cells ; Cells, Cultured ; cholesterol ; DNA-Binding Proteins - metabolism ; Egr-1 protein ; gene expression ; Gene Expression Regulation - drug effects ; genetic regulation ; Humans ; Kinetics ; Lipopolysaccharides - pharmacology ; Lipoproteins, LDL - pharmacology ; low density lipoprotein ; messenger RNA ; Molecular Sequence Data ; Muscle, Smooth, Vascular - drug effects ; Muscle, Smooth, Vascular - metabolism ; Mutation ; Nuclear Proteins - metabolism ; oxidation ; promoter regions ; Promoter Regions, Genetic ; Rabbits ; Rats ; Receptors, LDL - metabolism ; smooth muscle ; TF gene ; Thromboplastin - biosynthesis ; Thromboplastin - genetics ; tissue factor ; transcription factors ; Transcriptional Activation ; Transfection</subject><ispartof>The Journal of biological chemistry, 1999-11, Vol.274 (46), p.32795-32802</ispartof><rights>1999 © 1999 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c538t-92a3cc090c852bedf018a70b6597765b37fca18dbd4145d097d89e3be27b58c53</citedby><cites>FETCH-LOGICAL-c538t-92a3cc090c852bedf018a70b6597765b37fca18dbd4145d097d89e3be27b58c53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10551840$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cui, Mei-Zhen</creatorcontrib><creatorcontrib>Penn, Marc S.</creatorcontrib><creatorcontrib>Chisolm, Guy M.</creatorcontrib><title>Native and Oxidized Low Density Lipoprotein Induction of Tissue Factor Gene Expression in Smooth Muscle Cells Is Mediated by Both Egr-1 and Sp1</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Tissue factor, in association with factor VIIa, initiates the coagulation cascade. We studied the influences of two pathophysiological stimuli, native (unmodified) and oxidized low density lipoprotein, on tissue factor gene expression in a cell important in vascular remodeling and vascular diseases, the smooth muscle cell. Our results demonstrated that both lipoproteins significantly induced tissue factor gene expression in rat aortic smooth muscle cells; oxidized low density lipoprotein was slightly more potent. Both lipoproteins increased tissue factor mRNA in a concentration- and time-dependent manner. Results from nuclear run-on assays and mRNA stability experiments indicated that increased tissue factor mRNA accumulation in response to the lipoproteins was principally controlled at the transcriptional level. By using lipid extracts of low density lipoprotein or methylation of the intact lipoprotein to block receptor recognition, we showed that this lipoprotein induced tissue factor mRNA via both receptor-independent and receptor-augmented pathways. Transfection studies using a series of deleted tissue factor promoters revealed that a −143- to +106-base pair region of the rat tissue factor promoter contained regulatory elements required for lipoprotein-mediated induction. Electrophoretic mobility shift assays showed that the binding activities of the transcription factor Egr-1, but not Sp1, were markedly elevated in response to these lipoproteins. Transfection of site-directed mutants of the tissue factor (TF) promoter demonstrated that not only Egr-1 but also Sp1 cis-acting elements in the TF (−143) promoter construct were necessary for optimal TF gene induction. Our data show for the first time that both low density lipoprotein and oxidized low density lipoprotein induce tissue factor gene expression in smooth muscle cells and that this tissue factor gene expression is mediated by both Egr-1 and Sp1 transcription factors.</description><subject>Animals</subject><subject>aorta</subject><subject>Base Sequence</subject><subject>binding</subject><subject>blood coagulation factors</subject><subject>cells</subject><subject>Cells, Cultured</subject><subject>cholesterol</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Egr-1 protein</subject><subject>gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>genetic regulation</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Lipoproteins, LDL - pharmacology</subject><subject>low density lipoprotein</subject><subject>messenger RNA</subject><subject>Molecular Sequence Data</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Mutation</subject><subject>Nuclear Proteins - metabolism</subject><subject>oxidation</subject><subject>promoter regions</subject><subject>Promoter Regions, Genetic</subject><subject>Rabbits</subject><subject>Rats</subject><subject>Receptors, LDL - metabolism</subject><subject>smooth muscle</subject><subject>TF gene</subject><subject>Thromboplastin - biosynthesis</subject><subject>Thromboplastin - genetics</subject><subject>tissue factor</subject><subject>transcription factors</subject><subject>Transcriptional Activation</subject><subject>Transfection</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kUtvEzEUhS0EoqGwZwVeIHYT7Bl7HuwgpCVSShdpJXaWH3cSV5nx1Pa0DX-Cv4zT6QIh4c3dfPf43HMQekvJnJKKfbpRep5XbM7KeZFXDX-GZpTURVZw-vM5mhGS06zJeX2CXoVwQ9JjDX2JTijhnNaMzNDvHzLaO8CyN_jywRr7Cwxeu3v8Dfpg4wGv7eAG7yLYHq96M-poXY9di69sCCPgM6mj8_gcesDLh8FDCEcg0ZvOubjDF2PQe8AL2O8DXgV8AcbKmH5RB_z1CCy3PqOPBjYDfY1etHIf4M3TPEXXZ8urxfdsfXm-WnxZZ5oXdUxHyUJr0hBd81yBaQmtZUVUyZuqKrkqqlZLWhtlGGXckKYydQOFgrxSvE4ap-jjpJtuux0hRNHZoJNH2YMbg6AV4zWhZQLJBGrvQvDQisHbTvqDoEQcSxCpBJFKEKwUjyWklXdP2qPqwPy1MKWegA8TsLPb3b31IJR1egfdvzrvJ6yVTsitt0Fcb3JCC5I3LC_zo7nPEwEpqjsLXgRtodcpYg86CuPs_23-ASsJq4c</recordid><startdate>19991112</startdate><enddate>19991112</enddate><creator>Cui, Mei-Zhen</creator><creator>Penn, Marc S.</creator><creator>Chisolm, Guy M.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><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>7TM</scope></search><sort><creationdate>19991112</creationdate><title>Native and Oxidized Low Density Lipoprotein Induction of Tissue Factor Gene Expression in Smooth Muscle Cells Is Mediated by Both Egr-1 and Sp1</title><author>Cui, Mei-Zhen ; Penn, Marc S. ; Chisolm, Guy M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c538t-92a3cc090c852bedf018a70b6597765b37fca18dbd4145d097d89e3be27b58c53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Animals</topic><topic>aorta</topic><topic>Base Sequence</topic><topic>binding</topic><topic>blood coagulation factors</topic><topic>cells</topic><topic>Cells, Cultured</topic><topic>cholesterol</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Egr-1 protein</topic><topic>gene expression</topic><topic>Gene Expression Regulation - drug effects</topic><topic>genetic regulation</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Lipoproteins, LDL - pharmacology</topic><topic>low density lipoprotein</topic><topic>messenger RNA</topic><topic>Molecular Sequence Data</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Mutation</topic><topic>Nuclear Proteins - metabolism</topic><topic>oxidation</topic><topic>promoter regions</topic><topic>Promoter Regions, Genetic</topic><topic>Rabbits</topic><topic>Rats</topic><topic>Receptors, LDL - metabolism</topic><topic>smooth muscle</topic><topic>TF gene</topic><topic>Thromboplastin - biosynthesis</topic><topic>Thromboplastin - genetics</topic><topic>tissue factor</topic><topic>transcription factors</topic><topic>Transcriptional Activation</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cui, Mei-Zhen</creatorcontrib><creatorcontrib>Penn, Marc S.</creatorcontrib><creatorcontrib>Chisolm, Guy M.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cui, Mei-Zhen</au><au>Penn, Marc S.</au><au>Chisolm, Guy M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Native and Oxidized Low Density Lipoprotein Induction of Tissue Factor Gene Expression in Smooth Muscle Cells Is Mediated by Both Egr-1 and Sp1</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>1999-11-12</date><risdate>1999</risdate><volume>274</volume><issue>46</issue><spage>32795</spage><epage>32802</epage><pages>32795-32802</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Tissue factor, in association with factor VIIa, initiates the coagulation cascade. We studied the influences of two pathophysiological stimuli, native (unmodified) and oxidized low density lipoprotein, on tissue factor gene expression in a cell important in vascular remodeling and vascular diseases, the smooth muscle cell. Our results demonstrated that both lipoproteins significantly induced tissue factor gene expression in rat aortic smooth muscle cells; oxidized low density lipoprotein was slightly more potent. Both lipoproteins increased tissue factor mRNA in a concentration- and time-dependent manner. Results from nuclear run-on assays and mRNA stability experiments indicated that increased tissue factor mRNA accumulation in response to the lipoproteins was principally controlled at the transcriptional level. By using lipid extracts of low density lipoprotein or methylation of the intact lipoprotein to block receptor recognition, we showed that this lipoprotein induced tissue factor mRNA via both receptor-independent and receptor-augmented pathways. Transfection studies using a series of deleted tissue factor promoters revealed that a −143- to +106-base pair region of the rat tissue factor promoter contained regulatory elements required for lipoprotein-mediated induction. Electrophoretic mobility shift assays showed that the binding activities of the transcription factor Egr-1, but not Sp1, were markedly elevated in response to these lipoproteins. Transfection of site-directed mutants of the tissue factor (TF) promoter demonstrated that not only Egr-1 but also Sp1 cis-acting elements in the TF (−143) promoter construct were necessary for optimal TF gene induction. Our data show for the first time that both low density lipoprotein and oxidized low density lipoprotein induce tissue factor gene expression in smooth muscle cells and that this tissue factor gene expression is mediated by both Egr-1 and Sp1 transcription factors.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>10551840</pmid><doi>10.1074/jbc.274.46.32795</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 1999-11, Vol.274 (46), p.32795-32802 |
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| subjects | Animals aorta Base Sequence binding blood coagulation factors cells Cells, Cultured cholesterol DNA-Binding Proteins - metabolism Egr-1 protein gene expression Gene Expression Regulation - drug effects genetic regulation Humans Kinetics Lipopolysaccharides - pharmacology Lipoproteins, LDL - pharmacology low density lipoprotein messenger RNA Molecular Sequence Data Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - metabolism Mutation Nuclear Proteins - metabolism oxidation promoter regions Promoter Regions, Genetic Rabbits Rats Receptors, LDL - metabolism smooth muscle TF gene Thromboplastin - biosynthesis Thromboplastin - genetics tissue factor transcription factors Transcriptional Activation Transfection |
| title | Native and Oxidized Low Density Lipoprotein Induction of Tissue Factor Gene Expression in Smooth Muscle Cells Is Mediated by Both Egr-1 and Sp1 |
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