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Ligand activation of peroxisome proliferator‐activated receptor delta suppresses cathepsin B expression in human endothelial cells in a posttranslational manner
Author(s) -
Reichenbach Gabi,
StarzinskiPowitz Anna,
Doll Monika,
Hrgovic Igor,
Maria Valesky Eva,
Kippenberger Stefan,
Bernd August,
Kaufmann Roland,
Meissner Markus
Publication year - 2012
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12002
Subject(s) - peroxisome proliferator activated receptor , cathepsin , receptor , chemistry , cathepsin b , cathepsin d , microbiology and biotechnology , downregulation and upregulation , cancer research , biology , biochemistry , enzyme , gene
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 PPAR δ agonists. This study reveals an inhibitory effect of two commonly used PPAR δ agonists, GW 501516 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 PPAR δ agonists. Furthermore, the results substantiate that PPAR δ activators mediate their inhibitory action in a PPAR δ‐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 mi RNA could be excluded. The data of this study explore cathepsin B as a new valid target for PPAR δ agonists in endothelial cells. The results bolster other studies demonstrating PPAR δ agonists as anti‐inflammatory and anticarcinogenic agents and thus might have the potential to help to develop new pharmaceutical drugs.