Perturbation in Cardiac Energy Metabolism is Linked to Radiation-induced Heart Disease

Abstract

Radiation exposure to the thorax is associated with a markedly increased risk of cardiac morbidity and mortality with a latency period of [1-4]. Although many studies have confirmed the damaging effect of ionizing radiation on the myocardium and cardiac endothelial structure and function, the molecular mechanism behind this damage is not yet elucidated. As cardiac function greatly depends on mitochondrial metabolic activity we investigated radiation-induced cardiac metabolism disordering in general and the role of Peroxisome proliferator-activated receptor alpha (PPAR alpha) in this process in particular. C57BL/6N mice were locally irradiated to the heart at the age of 8 weeks using X-ray doses of 8 and 16 Gy. The mice were sacrificed 16 weeks after irradiation and the changes in the cardiac proteome were quantified using Isotope Coded Protein Label (ICPL). The proteomics data were further analysed using transcriptomics, immunoblotting, bioinformatics, immunohistochemistry, electron microscopy and serum lipid profiling. Significant alterations were observed in proteins involved in cardiac lipid metabolism and mitochondrial oxidative phosphorylation. Ionizing radiation markedly changed the mitochondrial structure and size, characterized by the loss of the mitochondrial matrix. Irradiation increased phosphorylation and ubiquitination status of PPAR alpha resulting in decreased expression of its target proteins involved in energy metabolism and mitochondrial respiratory chain. This study suggests that persistent alteration of cardiac metabolism due to impaired PPAR alpha activity contributes to the heart pathology after radiation activity activity [5].