Involvement of RAGE, NADPH Oxidase, and Ras/Raf-1 Pathway in Glycated LDL-Induced Expression of Heat Shock Factor-1 and Plasminogen Activator Inhibitor-1 in Vascular Endothelial Cells

Atherothrombotic cardiovascular diseases are the predominant causes of mortality of diabetic patients. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor for fibrinolysis, and it is also implicated in inflammation and tissue remodeling. Increased levels of PAI-1 and glyca...

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Veröffentlicht in:Endocrinology (Philadelphia) 2010-09, Vol.151 (9), p.4455-4466
Hauptverfasser: Sangle, Ganesh V, Zhao, Ruozhi, Mizuno, Tooru M, Shen, Garry X
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Zhao, Ruozhi
Mizuno, Tooru M
Shen, Garry X
description Atherothrombotic cardiovascular diseases are the predominant causes of mortality of diabetic patients. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor for fibrinolysis, and it is also implicated in inflammation and tissue remodeling. Increased levels of PAI-1 and glycated low-density lipoprotein (glyLDL) were detected in patients with diabetes. Previous studies in our laboratory demonstrated that heat shock factor-1 (HSF1) is involved in glyLDL-induced PAI-1 overproduction in vascular endothelial cells (EC). The present study investigated transmembrane signaling mechanisms involved in glyLDL-induced HSF1 and PAI-1 up-regulation in cultured human vascular EC and streptozotocin-induced diabetic mice. Receptor for advanced glycation end products (RAGE) antibody prevented glyLDL-induced increase in the abundance of PAI-1 in EC. GlyLDL significantly increased the translocation of V-Ha-Ras Harvey rat sarcoma viral oncogene homologue (H-Ras) from cytoplasm to membrane compared with LDL. Farnesyltransferase inhibitor-277 or small interference RNA against H-Ras inhibited glyLDL-induced increases in HSF1 and PAI-1 in EC. Treatment with diphenyleneiodonium, a nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor, blocked glyLDL-induced translocation of H-Ras, elevated abundances of HSF1 and PAI-1 in EC, and increased release of hydrogen peroxide from EC. Small interference RNA for p22phox prevented glyLDL-induced expression of NOX2, HSF1, and PAI-1 in EC. GlyLDL significantly increased V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) phosphorylation. Treatment with Raf-1 inhibitor blocked glyLDL-induced increase of PAI-1 mRNA in EC. The levels of RAGE, H-Ras, NOX4, HSF1, and PAI-1 were increased in hearts of streptozotocin-diabetic mice and positively correlated with plasma glucose. The results suggest that RAGE, NOX, and H-Ras/Raf-1 are implicated in the up-regulation of HSF1 or PAI-1 in vascular EC under diabetes-associated metabolic stress. Glycated LDL stimulates the expression of plasminogen activator inhibitor-1 in vascular endothelial cells through the activation of receptor of AGEs, H-Ras, Raf1, and NADPH oxidase.
doi_str_mv 10.1210/en.2010-0323
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Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor for fibrinolysis, and it is also implicated in inflammation and tissue remodeling. Increased levels of PAI-1 and glycated low-density lipoprotein (glyLDL) were detected in patients with diabetes. Previous studies in our laboratory demonstrated that heat shock factor-1 (HSF1) is involved in glyLDL-induced PAI-1 overproduction in vascular endothelial cells (EC). The present study investigated transmembrane signaling mechanisms involved in glyLDL-induced HSF1 and PAI-1 up-regulation in cultured human vascular EC and streptozotocin-induced diabetic mice. Receptor for advanced glycation end products (RAGE) antibody prevented glyLDL-induced increase in the abundance of PAI-1 in EC. GlyLDL significantly increased the translocation of V-Ha-Ras Harvey rat sarcoma viral oncogene homologue (H-Ras) from cytoplasm to membrane compared with LDL. Farnesyltransferase inhibitor-277 or small interference RNA against H-Ras inhibited glyLDL-induced increases in HSF1 and PAI-1 in EC. Treatment with diphenyleneiodonium, a nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor, blocked glyLDL-induced translocation of H-Ras, elevated abundances of HSF1 and PAI-1 in EC, and increased release of hydrogen peroxide from EC. Small interference RNA for p22phox prevented glyLDL-induced expression of NOX2, HSF1, and PAI-1 in EC. GlyLDL significantly increased V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) phosphorylation. Treatment with Raf-1 inhibitor blocked glyLDL-induced increase of PAI-1 mRNA in EC. The levels of RAGE, H-Ras, NOX4, HSF1, and PAI-1 were increased in hearts of streptozotocin-diabetic mice and positively correlated with plasma glucose. The results suggest that RAGE, NOX, and H-Ras/Raf-1 are implicated in the up-regulation of HSF1 or PAI-1 in vascular EC under diabetes-associated metabolic stress. Glycated LDL stimulates the expression of plasminogen activator inhibitor-1 in vascular endothelial cells through the activation of receptor of AGEs, H-Ras, Raf1, and NADPH oxidase.</description><identifier>ISSN: 0013-7227</identifier><identifier>EISSN: 1945-7170</identifier><identifier>DOI: 10.1210/en.2010-0323</identifier><identifier>PMID: 20630999</identifier><identifier>CODEN: ENDOAO</identifier><language>eng</language><publisher>Chevy Chase, MD: Endocrine Society</publisher><subject>Adenine ; Advanced glycosylation end products ; Animals ; Antibodies ; Antibodies - pharmacology ; Biological and medical sciences ; Blood Glucose - metabolism ; Blotting, Western ; Cardiovascular diseases ; Cell Line ; CYBB protein ; Cytoplasm ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental - blood ; Diabetes Mellitus, Experimental - chemically induced ; Diabetes Mellitus, Experimental - metabolism ; DNA-Binding Proteins - metabolism ; Endothelial cells ; Endothelial Cells - cytology ; Endothelial Cells - drug effects ; Endothelial Cells - metabolism ; Farnesyl-diphosphate farnesyltransferase ; Farnesyltransferase ; Fibrinolysis ; Fundamental and applied biological sciences. Psychology ; Gene expression ; Glucose ; H-Ras protein ; Heart ; Heat shock ; Heat shock factors ; Heat Shock Transcription Factors ; HSF1 protein ; Humans ; Hydrogen peroxide ; Leukemia ; Lipoproteins ; Lipoproteins (low density) ; Lipoproteins, LDL - pharmacology ; Low density lipoprotein ; Male ; Mice ; Mice, Inbred C57BL ; Mortality ; mRNA ; NAD(P)H oxidase ; NADPH Oxidases - genetics ; NADPH Oxidases - metabolism ; NADPH-diaphorase ; Nicotinamide ; Nicotinamide adenine dinucleotide ; NOX4 protein ; Oncogenes ; Onium Compounds - pharmacology ; Oxidase ; Phosphorylation ; Physiological effects ; plasminogen ; Plasminogen Activator Inhibitor 1 - genetics ; Plasminogen Activator Inhibitor 1 - metabolism ; Plasminogen activator inhibitors ; Proto-Oncogene Proteins c-raf - metabolism ; Raf protein ; Ras protein ; ras Proteins - metabolism ; Receptor for Advanced Glycation End Products ; Receptors, Immunologic - immunology ; Receptors, Immunologic - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RNA Interference ; RNA-mediated interference ; Sarcoma ; Signal transduction ; Signal Transduction - drug effects ; siRNA ; Streptozocin ; Stress ; Transcription Factors - metabolism ; Translocation ; Up-regulation ; Vertebrates: endocrinology</subject><ispartof>Endocrinology (Philadelphia), 2010-09, Vol.151 (9), p.4455-4466</ispartof><rights>Copyright © 2010 by The Endocrine Society 2010</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2010 by The Endocrine Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-b62a6422b9e973dd17c6e38a92784a749545cc9d09298af8aae759ef91acdcec3</citedby><cites>FETCH-LOGICAL-c592t-b62a6422b9e973dd17c6e38a92784a749545cc9d09298af8aae759ef91acdcec3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=24024355$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20630999$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sangle, Ganesh V</creatorcontrib><creatorcontrib>Zhao, Ruozhi</creatorcontrib><creatorcontrib>Mizuno, Tooru M</creatorcontrib><creatorcontrib>Shen, Garry X</creatorcontrib><title>Involvement of RAGE, NADPH Oxidase, and Ras/Raf-1 Pathway in Glycated LDL-Induced Expression of Heat Shock Factor-1 and Plasminogen Activator Inhibitor-1 in Vascular Endothelial Cells</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><description>Atherothrombotic cardiovascular diseases are the predominant causes of mortality of diabetic patients. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor for fibrinolysis, and it is also implicated in inflammation and tissue remodeling. Increased levels of PAI-1 and glycated low-density lipoprotein (glyLDL) were detected in patients with diabetes. Previous studies in our laboratory demonstrated that heat shock factor-1 (HSF1) is involved in glyLDL-induced PAI-1 overproduction in vascular endothelial cells (EC). The present study investigated transmembrane signaling mechanisms involved in glyLDL-induced HSF1 and PAI-1 up-regulation in cultured human vascular EC and streptozotocin-induced diabetic mice. Receptor for advanced glycation end products (RAGE) antibody prevented glyLDL-induced increase in the abundance of PAI-1 in EC. GlyLDL significantly increased the translocation of V-Ha-Ras Harvey rat sarcoma viral oncogene homologue (H-Ras) from cytoplasm to membrane compared with LDL. Farnesyltransferase inhibitor-277 or small interference RNA against H-Ras inhibited glyLDL-induced increases in HSF1 and PAI-1 in EC. Treatment with diphenyleneiodonium, a nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor, blocked glyLDL-induced translocation of H-Ras, elevated abundances of HSF1 and PAI-1 in EC, and increased release of hydrogen peroxide from EC. Small interference RNA for p22phox prevented glyLDL-induced expression of NOX2, HSF1, and PAI-1 in EC. GlyLDL significantly increased V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) phosphorylation. Treatment with Raf-1 inhibitor blocked glyLDL-induced increase of PAI-1 mRNA in EC. The levels of RAGE, H-Ras, NOX4, HSF1, and PAI-1 were increased in hearts of streptozotocin-diabetic mice and positively correlated with plasma glucose. The results suggest that RAGE, NOX, and H-Ras/Raf-1 are implicated in the up-regulation of HSF1 or PAI-1 in vascular EC under diabetes-associated metabolic stress. Glycated LDL stimulates the expression of plasminogen activator inhibitor-1 in vascular endothelial cells through the activation of receptor of AGEs, H-Ras, Raf1, and NADPH oxidase.</description><subject>Adenine</subject><subject>Advanced glycosylation end products</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antibodies - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Blood Glucose - metabolism</subject><subject>Blotting, Western</subject><subject>Cardiovascular diseases</subject><subject>Cell Line</subject><subject>CYBB protein</subject><subject>Cytoplasm</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Experimental - blood</subject><subject>Diabetes Mellitus, Experimental - chemically induced</subject><subject>Diabetes Mellitus, Experimental - metabolism</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - cytology</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - metabolism</subject><subject>Farnesyl-diphosphate farnesyltransferase</subject><subject>Farnesyltransferase</subject><subject>Fibrinolysis</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene expression</subject><subject>Glucose</subject><subject>H-Ras protein</subject><subject>Heart</subject><subject>Heat shock</subject><subject>Heat shock factors</subject><subject>Heat Shock Transcription Factors</subject><subject>HSF1 protein</subject><subject>Humans</subject><subject>Hydrogen peroxide</subject><subject>Leukemia</subject><subject>Lipoproteins</subject><subject>Lipoproteins (low density)</subject><subject>Lipoproteins, LDL - pharmacology</subject><subject>Low density lipoprotein</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mortality</subject><subject>mRNA</subject><subject>NAD(P)H oxidase</subject><subject>NADPH Oxidases - genetics</subject><subject>NADPH Oxidases - metabolism</subject><subject>NADPH-diaphorase</subject><subject>Nicotinamide</subject><subject>Nicotinamide adenine dinucleotide</subject><subject>NOX4 protein</subject><subject>Oncogenes</subject><subject>Onium Compounds - pharmacology</subject><subject>Oxidase</subject><subject>Phosphorylation</subject><subject>Physiological effects</subject><subject>plasminogen</subject><subject>Plasminogen Activator Inhibitor 1 - genetics</subject><subject>Plasminogen Activator Inhibitor 1 - metabolism</subject><subject>Plasminogen activator inhibitors</subject><subject>Proto-Oncogene Proteins c-raf - metabolism</subject><subject>Raf protein</subject><subject>Ras protein</subject><subject>ras Proteins - metabolism</subject><subject>Receptor for Advanced Glycation End Products</subject><subject>Receptors, Immunologic - immunology</subject><subject>Receptors, Immunologic - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA Interference</subject><subject>RNA-mediated interference</subject><subject>Sarcoma</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>siRNA</subject><subject>Streptozocin</subject><subject>Stress</subject><subject>Transcription Factors - metabolism</subject><subject>Translocation</subject><subject>Up-regulation</subject><subject>Vertebrates: endocrinology</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU2P0zAQhiMEYsvCjTOyhBCXZtdf-fCx6nbbShVblY9rNHUm1Etqlzgp21_G38OhhUoIJE62NY-emfEbRS8ZvWKc0Wu0V5wyGlPBxaNowJRM4oxl9HE0oJSJOOM8u4ieeX8fnlJK8TS64DQVVCk1iL7P7d7Ve9yibYmryGo0nQzJu9HNckbuHkwJHocEbElW4K9XUMWMLKHdfIMDMZZM64OGFkuyuFnEc1t2OtwnD7sGvTfO9sIZQkveb5z-Qm5Bt64Jht63rMFvjXWf0ZKRbs0eQo3M7caszZEK_k_gdVdDQya2dO0GawM1GWNd--fRkwpqjy9O52X08XbyYTyLF3fT-Xi0iHWieBuvUw6p5HytUGWiLFmmUxQ5KJ7lEjKpEplorUqquMqhygEwSxRWioEuNWpxGb09eneN-9qhb4ut8TpMABZd5wtFM5bIVMn_ImUuqQjk6z_Ie9c1NqxRCCZoynKWJoEaHindOO8brIpdY7bQHApGiz75Am3RJ1_0yQf81UnarbdY_oZ_RR2ANycgfCrUVQNWG3_mJOVSJMl5D9ft_tUyPrUURxJDOroxFn8Gf97mr4P-ACt20X8</recordid><startdate>20100901</startdate><enddate>20100901</enddate><creator>Sangle, Ganesh V</creator><creator>Zhao, Ruozhi</creator><creator>Mizuno, Tooru M</creator><creator>Shen, Garry X</creator><general>Endocrine Society</general><general>Oxford University Press</general><scope>IQODW</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>7QG</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope></search><sort><creationdate>20100901</creationdate><title>Involvement of RAGE, NADPH Oxidase, and Ras/Raf-1 Pathway in Glycated LDL-Induced Expression of Heat Shock Factor-1 and Plasminogen Activator Inhibitor-1 in Vascular Endothelial Cells</title><author>Sangle, Ganesh V ; Zhao, Ruozhi ; Mizuno, Tooru M ; Shen, Garry X</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-b62a6422b9e973dd17c6e38a92784a749545cc9d09298af8aae759ef91acdcec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adenine</topic><topic>Advanced glycosylation end products</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antibodies - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Blood Glucose - metabolism</topic><topic>Blotting, Western</topic><topic>Cardiovascular diseases</topic><topic>Cell Line</topic><topic>CYBB protein</topic><topic>Cytoplasm</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Experimental - blood</topic><topic>Diabetes Mellitus, Experimental - chemically induced</topic><topic>Diabetes Mellitus, Experimental - metabolism</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - cytology</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - metabolism</topic><topic>Farnesyl-diphosphate farnesyltransferase</topic><topic>Farnesyltransferase</topic><topic>Fibrinolysis</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene expression</topic><topic>Glucose</topic><topic>H-Ras protein</topic><topic>Heart</topic><topic>Heat shock</topic><topic>Heat shock factors</topic><topic>Heat Shock Transcription Factors</topic><topic>HSF1 protein</topic><topic>Humans</topic><topic>Hydrogen peroxide</topic><topic>Leukemia</topic><topic>Lipoproteins</topic><topic>Lipoproteins (low density)</topic><topic>Lipoproteins, LDL - pharmacology</topic><topic>Low density lipoprotein</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mortality</topic><topic>mRNA</topic><topic>NAD(P)H oxidase</topic><topic>NADPH Oxidases - genetics</topic><topic>NADPH Oxidases - metabolism</topic><topic>NADPH-diaphorase</topic><topic>Nicotinamide</topic><topic>Nicotinamide adenine dinucleotide</topic><topic>NOX4 protein</topic><topic>Oncogenes</topic><topic>Onium Compounds - pharmacology</topic><topic>Oxidase</topic><topic>Phosphorylation</topic><topic>Physiological effects</topic><topic>plasminogen</topic><topic>Plasminogen Activator Inhibitor 1 - genetics</topic><topic>Plasminogen Activator Inhibitor 1 - metabolism</topic><topic>Plasminogen activator inhibitors</topic><topic>Proto-Oncogene Proteins c-raf - metabolism</topic><topic>Raf protein</topic><topic>Ras protein</topic><topic>ras Proteins - metabolism</topic><topic>Receptor for Advanced Glycation End Products</topic><topic>Receptors, Immunologic - immunology</topic><topic>Receptors, Immunologic - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA Interference</topic><topic>RNA-mediated interference</topic><topic>Sarcoma</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>siRNA</topic><topic>Streptozocin</topic><topic>Stress</topic><topic>Transcription Factors - metabolism</topic><topic>Translocation</topic><topic>Up-regulation</topic><topic>Vertebrates: endocrinology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sangle, Ganesh V</creatorcontrib><creatorcontrib>Zhao, Ruozhi</creatorcontrib><creatorcontrib>Mizuno, Tooru M</creatorcontrib><creatorcontrib>Shen, Garry X</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Endocrinology (Philadelphia)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sangle, Ganesh V</au><au>Zhao, Ruozhi</au><au>Mizuno, Tooru M</au><au>Shen, Garry X</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Involvement of RAGE, NADPH Oxidase, and Ras/Raf-1 Pathway in Glycated LDL-Induced Expression of Heat Shock Factor-1 and Plasminogen Activator Inhibitor-1 in Vascular Endothelial Cells</atitle><jtitle>Endocrinology (Philadelphia)</jtitle><addtitle>Endocrinology</addtitle><date>2010-09-01</date><risdate>2010</risdate><volume>151</volume><issue>9</issue><spage>4455</spage><epage>4466</epage><pages>4455-4466</pages><issn>0013-7227</issn><eissn>1945-7170</eissn><coden>ENDOAO</coden><abstract>Atherothrombotic cardiovascular diseases are the predominant causes of mortality of diabetic patients. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor for fibrinolysis, and it is also implicated in inflammation and tissue remodeling. Increased levels of PAI-1 and glycated low-density lipoprotein (glyLDL) were detected in patients with diabetes. Previous studies in our laboratory demonstrated that heat shock factor-1 (HSF1) is involved in glyLDL-induced PAI-1 overproduction in vascular endothelial cells (EC). The present study investigated transmembrane signaling mechanisms involved in glyLDL-induced HSF1 and PAI-1 up-regulation in cultured human vascular EC and streptozotocin-induced diabetic mice. Receptor for advanced glycation end products (RAGE) antibody prevented glyLDL-induced increase in the abundance of PAI-1 in EC. GlyLDL significantly increased the translocation of V-Ha-Ras Harvey rat sarcoma viral oncogene homologue (H-Ras) from cytoplasm to membrane compared with LDL. Farnesyltransferase inhibitor-277 or small interference RNA against H-Ras inhibited glyLDL-induced increases in HSF1 and PAI-1 in EC. Treatment with diphenyleneiodonium, a nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor, blocked glyLDL-induced translocation of H-Ras, elevated abundances of HSF1 and PAI-1 in EC, and increased release of hydrogen peroxide from EC. Small interference RNA for p22phox prevented glyLDL-induced expression of NOX2, HSF1, and PAI-1 in EC. GlyLDL significantly increased V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) phosphorylation. Treatment with Raf-1 inhibitor blocked glyLDL-induced increase of PAI-1 mRNA in EC. The levels of RAGE, H-Ras, NOX4, HSF1, and PAI-1 were increased in hearts of streptozotocin-diabetic mice and positively correlated with plasma glucose. The results suggest that RAGE, NOX, and H-Ras/Raf-1 are implicated in the up-regulation of HSF1 or PAI-1 in vascular EC under diabetes-associated metabolic stress. Glycated LDL stimulates the expression of plasminogen activator inhibitor-1 in vascular endothelial cells through the activation of receptor of AGEs, H-Ras, Raf1, and NADPH oxidase.</abstract><cop>Chevy Chase, MD</cop><pub>Endocrine Society</pub><pmid>20630999</pmid><doi>10.1210/en.2010-0323</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection
subjects Adenine
Advanced glycosylation end products
Animals
Antibodies
Antibodies - pharmacology
Biological and medical sciences
Blood Glucose - metabolism
Blotting, Western
Cardiovascular diseases
Cell Line
CYBB protein
Cytoplasm
Diabetes
Diabetes mellitus
Diabetes Mellitus, Experimental - blood
Diabetes Mellitus, Experimental - chemically induced
Diabetes Mellitus, Experimental - metabolism
DNA-Binding Proteins - metabolism
Endothelial cells
Endothelial Cells - cytology
Endothelial Cells - drug effects
Endothelial Cells - metabolism
Farnesyl-diphosphate farnesyltransferase
Farnesyltransferase
Fibrinolysis
Fundamental and applied biological sciences. Psychology
Gene expression
Glucose
H-Ras protein
Heart
Heat shock
Heat shock factors
Heat Shock Transcription Factors
HSF1 protein
Humans
Hydrogen peroxide
Leukemia
Lipoproteins
Lipoproteins (low density)
Lipoproteins, LDL - pharmacology
Low density lipoprotein
Male
Mice
Mice, Inbred C57BL
Mortality
mRNA
NAD(P)H oxidase
NADPH Oxidases - genetics
NADPH Oxidases - metabolism
NADPH-diaphorase
Nicotinamide
Nicotinamide adenine dinucleotide
NOX4 protein
Oncogenes
Onium Compounds - pharmacology
Oxidase
Phosphorylation
Physiological effects
plasminogen
Plasminogen Activator Inhibitor 1 - genetics
Plasminogen Activator Inhibitor 1 - metabolism
Plasminogen activator inhibitors
Proto-Oncogene Proteins c-raf - metabolism
Raf protein
Ras protein
ras Proteins - metabolism
Receptor for Advanced Glycation End Products
Receptors, Immunologic - immunology
Receptors, Immunologic - metabolism
Reverse Transcriptase Polymerase Chain Reaction
RNA Interference
RNA-mediated interference
Sarcoma
Signal transduction
Signal Transduction - drug effects
siRNA
Streptozocin
Stress
Transcription Factors - metabolism
Translocation
Up-regulation
Vertebrates: endocrinology
title Involvement of RAGE, NADPH Oxidase, and Ras/Raf-1 Pathway in Glycated LDL-Induced Expression of Heat Shock Factor-1 and Plasminogen Activator Inhibitor-1 in Vascular Endothelial Cells
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