title: PPARalpha activators inhibit vascular endothelial growth factor receptor-2 expression by repressing Sp1-dependent DNA binding and transactivation.
abstract: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, originally implicated in the regulation of lipid and glucose homeostasis. In addition, natural and synthetic PPAR activators may control inflammatory processes by inhibition of distinct proinflammatory genes. As signaling via the vascular endothelial growth factor receptor-2 (VEGFR2) pathway is critical for angiogenic responses during chronic inflammation, we explored whether known antiinflammatory effects of PPAR ligands are mediated in part through diminished VEGFR2 expression. In this study, PPARalpha agonists are found to inhibit endothelial VEGFR2 expression, whereas predominant PPARgamma ligands remained without discernible effects. Time- and concentration-dependent inhibition is demonstrated both at the level of protein and mRNA VEGFR2 expression. Inhibitory effects of PPARalpha agonists on transcriptional activity of the VEGFR2 promoter are conveyed by an element located between base pairs -60 and -37 that contains two adjacent consensus Sp1 transcription factor binding sites. Constitutive Sp1-containing complex formation to this sequence is decreased by PPARalpha treatment, indicating that VEGFR2 gene expression is inhibited by repressing Sp1 site-dependent DNA binding and transactivation. Our coimmunoprecipitation experiments revealed enhanced protein interactions between PPARalpha and Sp1 on PPARalpha activation, thus constituting a probable mechanism by which PPARalpha activators decrease Sp-dependent binding activity to the VEGFR2 promoter. Hence, molecular mechanisms by which PPARs modulate the rate of gene transcription may include direct interactions between specific transcription factors and PPARs that ultimately result in reduced DNA binding to their respective response elements.
authors.affiliation: Department of Dermatology, Klinikum der J.W. Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Meissner
authors.forename: Monika
authors.initials: M
authors.lastname: Stein
authors.forename: Carmen
authors.initials: C
authors.lastname: Urbich
authors.forename: Kerstin
authors.initials: K
authors.lastname: Reisinger
authors.forename: Guntram
authors.initials: G
authors.lastname: Suske
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Roland
authors.initials: R
authors.lastname: Kaufmann
authors.forename: Jens
authors.initials: J
authors.lastname: Gille
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D016329:Sp1 Transcription Factor; D045162:Thiazolidinediones; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000077154:Rosiglitazone; C006253:pirinixic acid; D008156:Luciferases; D040301:Vascular Endothelial Growth Factor Receptor-2; D011345:Fenofibrate; C039671:ciglitazone