PPARα Is Necessary for Radiation-Induced Activation of Noncanonical TGFβ Signaling in the Heart

TitlePPARα Is Necessary for Radiation-Induced Activation of Noncanonical TGFβ Signaling in the Heart
Publication TypeArticolo su Rivista peer-reviewed
Year of Publication2018
AuthorsSubramanian, Vikram, Borchard Sabine, Azimzadeh Omid, Sievert Wolfgang, Merl-Pham Juliane, Mancuso Mariateresa, Pasquali Emanuela, Multhoff Gabriele, Popper Bastian, Zischka Hans, Atkinson Michael J., and Tapio Soile
JournalJournal of Proteome Research
Volume17
Issue4
Pagination1677 - 1689
Date PublishedJun-04-2018
ISSN15353893
Abstract

High-dose ionizing radiation is known to induce adverse effects such as inflammation and fibrosis in the heart. Transcriptional regulators PPARα and TGFβ are known to be involved in this radiation response. PPARα, an anti-inflammatory transcription factor controlling cardiac energy metabolism, is inactivated by irradiation. The proinflammatory and pro-fibrotic TGFβ is activated by irradiation via SMAD-dependent and SMAD-independent pathways. The goal of this study was to investigate how altering the level of PPARα influences the radiation response of these signaling pathways. For this purpose, we used genetically modified C57Bl/6 mice with wild type (+/+), heterozygous (+/−) or homozygous (−/−) PPARα genotype. Mice were locally irradiated to the heart using doses of 8 or 16 Gy; the controls were sham-irradiated. The heart tissue was investigated using label-free proteomics 20 weeks after the irradiation and the predicted
pathways were validated using immunoblotting, ELISA, and immunohistochemistry. The heterozygous PPARα mice showed most radiation-induced changes in the cardiac proteome, whereas the homozygous PPARα mice showed the least changes. Irradiation induced SMAD-dependent TGFβ signaling independently of the PPARα status, but the presence of PPARα was necessary for the activation of the SMAD-independent pathway. These data indicate a central role of PPARα in cardiac response
to ionizing radiation.

URLhttp://pubs.acs.org/doi/10.1021/acs.jproteome.8b00001http://pubs.acs.org/doi/pdf/10.1021/acs.jproteome.8b00001
DOI10.1021/acs.jproteome.8b00001
Short TitleJ. Proteome Res.