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PPARα agonist Wy14643 suppresses cathepsin B in human endothelial cells via transcriptional, post-transcriptional and post-translational mechanisms

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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.

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Abbreviations

COX-2:

Cyclooxygenase-2

DMSO:

Dimethylsulfoxide

EMSA:

Electromobility shift assay

HUVEC:

Human umbilical vein endothelial cell

IκBα:

Inhibitor of kappa Bα

LPS:

Lipopolysaccharide

NF-κB:

Nuclear factor-kappa B

RT-PCR:

Reverse transcription polymerase chain reaction

USF:

Upstream stimulatory factor

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Acknowledgments

The study was supported by the Wilhelm Sander Foundation (MM) and the Berlin Foundation for Dermatology (MM) and by a grant from the University of Frankfurt (GR).

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Authors and Affiliations

  1. Department of Dermatology, Venereology and Allergology, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Gabi Reichenbach, Monika Doll, Stefan Kippenberger, August Bernd, Roland Kaufmann & Markus Meissner

  2. Department of Molecular Cell Biology and Human Genetics, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany

    Gabi Reichenbach & Anna Starzinski-Powitz

  3. Department of Pharmacology, Wayne State University, Detroit, MI, 48201, USA

    Bonnie F. Sloane

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  1. Gabi Reichenbach
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Reichenbach, G., Starzinski-Powitz, A., Sloane, B.F. et al. PPARα agonist Wy14643 suppresses cathepsin B in human endothelial cells via transcriptional, post-transcriptional and post-translational mechanisms. Angiogenesis 16, 223–233 (2013). https://doi.org/10.1007/s10456-012-9314-9

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