High-dose ionising radiation affects TGF beta and PPAR alpha signalling pathways 40 weeks after local heart irradiation in C57BL/6J mice

Epidemiological data from radiotherapy of thoracic and chest wall tumours show the damaging effect of ionising radiation on heart and vasculature. The long-term impairment of heart function and structure after local high-dose irradiation in mice is associated with systemic inflammatory response, contraction impairment, microvascular damage and cardiac fibrosis. The goal of the present study was to investigate molecular mechanisms involved in this process. C57BL/6J mice received X-ray doses of 8 and 16 Gy locally to the heart at the age of 8 weeks; the control mice were sham-irradiated. Radiation-induced changes in the heart transcriptome and proteome were investigated 40 weeks after the exposure using Illumina Expression Bead and Isotope Coded Protein Label technologies, respectively. The omics data were analysed by bioinformatics tools and validated by immunoblotting. The changes in the irradiated cardiac proteome indicated a perturbation of energy metabolism and its key regulator peroxisome proliferator-activated receptor (PPAR) alpha. Both proteomics and transcriptomics data predicted induction of transforming growth factor (TGF) beta signalling. The predicted mediator role of mitogen-activated protein (MAP) kinase cascade between PPAR alpha and TGF beta signalling pathways was analysed by immunoblotting. This study indicates that both pathways are involved in radiation-induced heart fibrosis, metabolic disordering and impaired contractility. These data are in line with the pathophysiological condition observed in patients that received high radiation doses in thorax.