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

Vikram Subramanian, Sabine Borchard, Omid Azimzadeh, Wolfgang Sievert, Juliane Merl-Pham, Mariateresa Mancuso, Emanuela Pasquali, Gabriele Multhoff, Bastian Popper, Hans Zischka, Michael J. Atkinson, Soile Tapio

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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 pro-inflammatory 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.
Original languageEnglish
Pages (from-to)1677 - 1689
Number of pages13
JournalJournal of Proteome Research
Volume17
Issue number4
DOIs
Publication statusPublished - 6 Apr 2018
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Chemistry(all)

Cite this

Subramanian, V., Borchard, S., Azimzadeh, O., Sievert, W., Merl-Pham, J., Mancuso, M., Pasquali, E., Multhoff, G., Popper, B., Zischka, H., Atkinson, M. J., & Tapio, S. (2018). PPARα Is Necessary for Radiation-Induced Activation of Noncanonical TGFβ Signaling in the Heart. Journal of Proteome Research, 17(4), 1677 - 1689. https://doi.org/10.1021/acs.jproteome.8b00001