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Subramanian, Vikram; Borchard, Sabine; Azimzadeh, Omid; Sievert, Wolfgang; Merl-Pham, Julian; Mancuso, Mariateresa; Pasquali, Emanuela; Multhoff, Gabriele; Popper, Bastian; Zischka, Hans; Atkinson, Michael J.; Tapio, Soile (2018): PPAR alpha Is Necessary for Radiation-Induced Activation of Noncanonical TGF beta Signaling in the Heart. In: Journal of Proteome Research, Vol. 17, No. 4: pp. 1677-1689
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High-dose ionizing radiation is known to induce adverse effects such as inflammation and fibrosis in the heart. Transcriptional regulators PPAR alpha and TGF beta are known to be involved in this radiation response. PPAR alpha, an anti-inflammatory transcription factor controlling cardiac energy metabolism, is inactivated by irradiation. The pro inflammatory and pro-fibrotic TGF beta is activated by irradiation via SMAD-dependent and SMAD-independent pathways. The goal of this study was to investigate how altering the level of PPAR alpha influences the radiation response of these signaling pathways. For this purpose, we used genetically modified C57Bl/6 mice with wild type (+/+), heterozygous (+/-) or homozygous (-/-) PPAR alpha 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 PPAR alpha mice showed most radiation-induced changes in the cardiac proteome, whereas the homozygous PPAR alpha mice showed the least changes. Irradiation induced SMAD-dependent TGF beta signaling independently of the PPAR alpha status, but the presence of PPAR alpha was necessary for the activation of the SMAD-independent pathway. These data indicate a central role of PPAR alpha in cardiac response to ionizing radiation.