Activation of PPAR alpha by fenofibrate attenuates the effect of local heart high dose irradiation on the mouse cardiac proteome

Radiation-induced cardiovascular disease is associated with the metabolic remodelling in the heart mainly due to disruption of the PPAR alpha signalling pathway and inhibition of lipid metabolic enzymes. The goal of the present study was to investigate the potential protective effect of fenofibrate-activation of PPARon radiation-induced cardiac toxicity. To this end, we compared, for the first time, the cardiac proteome of fenofibrate- and placebo-treated mice after local heart irradiation using label-free proteomics. The observations were further validated using immunoblotting, enzyme activity assays, and ELISA. The analysis showed that fenofibrate restores the affected pathways involved in lipid metabolism, mitochondrial function, oxidative stress damage, tissue remodelling and systematic inflammatory response. The results collectively presented here indicate that PPARactivation by fenofibrate attenuates the cardiac proteome alterations induced by irradiation. These findings suggest a potential benefit of PPAR alpha agonists administration in the prevention of cardiovascular diseases following radiotherapy.