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

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.