Ligand activation of peroxisome proliferator-activated receptor delta suppresses cathepsin B expression in human endothelial cells in a posttranslational manner.
Peroxisome proliferator-activated receptor (PPAR) delta agonists are known to have distinct anti-inflammatory and antitumor effects; though, the knowledge regarding their mode of action has thus far been limited. Different cathepsins have been shown to be upregulated in a broad range of pathological events, such as rheumatoid arthritis, psoriasis, atherosclerosis and diverse tumor entities, for example melanoma. Recent work demonstrated that cathepsin B in particular is an important pro-angiogenic protease in various pathological conditions. We therefore analysed whether cathepsins are a valid target for PPARδ agonists. This study reveals an inhibitory effect of two commonly used PPARδ agonists, GW501516 and L-165,041, on the protein expression and enzyme activity of cathepsin B in human endothelial cells. In contrast, no inhibitory effects were observed on cathepsin L and cathepsin D protein expression after treatment with PPARδ agonists. Furthermore, the results substantiate that PPARδ activators mediate their inhibitory action in a PPARδ-dependent manner and that the underlying regulatory mechanism is not based on a transcriptional but rather on a posttranslational mode of action, via the reduction in the cathepsin B protein half-life. Mechanisms conveying the suppressive effect by 5'-alternative splicing, a 3'-UTR-dependent way or by miRNA could be excluded. The data of this study explore cathepsin B as a new valid target for PPARδ agonists in endothelial cells. The results bolster other studies demonstrating PPARδ agonists as anti-inflammatory and anticarcinogenic agents and thus might have the potential to help to develop new pharmaceutical drugs.
Department of Dermatology, Venereology and Allergology, Frankfurt am Main, Germany.
Gabi
G
Reichenbach
Anna
A
Starzinski-Powitz
Monika
M
Doll
Igor
I
Hrgovic
Eva Maria
EM
Valesky
Stefan
S
Kippenberger
August
A
Bernd
Roland
R
Kaufmann
Markus
M
Meissner
D020413:3' Untranslated Regions; D001483:Base Sequence; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008024:Ligands; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D010642:Phenoxyacetates / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D043244:Ribonuclease III / Q000037:antagonists & inhibitors / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology
D020413:3' Untranslated Regions; C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; C425931:GW 501516; D008024:Ligands; D035683:MicroRNAs; D047494:PPAR delta; D010642:Phenoxyacetates; D034741:RNA, Small Interfering; D013844:Thiazoles; C408087:DICER1 protein, human; D043244:Ribonuclease III; C533912:CTSB protein, human; D002401:Cathepsin B; D053487:DEAD-box RNA Helicases