title: PPARα agonist Wy14643 suppresses cathepsin B in human endothelial cells via transcriptional, post-transcriptional and post-translational mechanisms.
abstract: Cathepsin B has been shown to be important in angiogenesis; therefore, understanding its regulation in endothelial cells should provide fundamental information that will aid in the development of new treatment options. Peroxisome proliferator-activated receptors (PPARs) have been shown to have anti-inflammatory, anti-angiogenic and anti-tumorigenic properties. We explored the influence of a PPARα agonist on cathepsin B expression in human endothelial cells. The PPARα agonist, Wy14643, was found to inhibit cathepsin B protein expression. Further studies demonstrated the Wy14643-dependent but PPARα-independent suppression of cathepsin B. This has been previously described for other PPAR agonists. Wy14643 suppressed the accumulation of cathepsin B mRNA, which was accompanied by the selective suppression of a 5'-alternative splice variant. Consistent with these results, luciferase promoter assays and electrophoretic mobility shift analysis demonstrated that the suppression was facilitated by reduced binding of the transcription factors USF1/2 to an E-box within the cathepsin B promoter. Additionally, Wy14643 treatment resulted in a reduction in cathepsin B half-life, suggesting a posttranslational regulatory mechanism. Overall, our results suggest that the PPARα-dependent anti-angiogenic action of Wy14643 seems to be mediated, in part, by Wy14643-dependent but PPARα-independent regulation of cathepsin B expression.
authors.affiliation: Department of Dermatology, Venereology and Allergology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors.forename: Gabi
authors.initials: G
authors.lastname: Reichenbach
authors.forename: Anna
authors.initials: A
authors.lastname: Starzinski-Powitz
authors.forename: Bonnie F
authors.initials: BF
authors.lastname: Sloane
authors.forename: Monika
authors.initials: M
authors.lastname: Doll
authors.forename: Stefan
authors.initials: S
authors.lastname: Kippenberger
authors.forename: August
authors.initials: A
authors.lastname: Bernd
authors.forename: Roland
authors.initials: R
authors.lastname: Kaufmann
authors.forename: Markus
authors.initials: M
authors.lastname: Meissner
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D020029:Base Pairing / Q000235:genetics; D015153:Blotting, Western; D002401:Cathepsin B / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D024721:E-Box Elements / Q000235:genetics; D005091:Exons / Q000235:genetics; D006207:Half-Life; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D014158:Transcription, Genetic / Q000187:drug effects*; D051720:Upstream Stimulatory Factors / Q000378:metabolism
chemical_list: D047493:PPAR alpha; D011743:Pyrimidines; D012333:RNA, Messenger; C497181:USF1 protein, human; C497184:USF2 protein, human; D051720:Upstream Stimulatory Factors; C006253:pirinixic acid; D002401:Cathepsin B