Radiation-induced heart energy metabolism dysfunction leads to heart fibrosis

Thoracic radiotherapy increases the risk of radiation-induced heart disease (RIHD), but its molecular mechanisms are not fully understood. We aimed to explore the effects of radiation on the mouse heart using high-throughput proteomics. An RIHD mouse model was established by exposing the whole heart to 16 Gy high-energy X-rays, and cardiac injuries were verified by cardiac echocardiogram, serum BNP, HE and Masson staining 5 months after irradiation. Proteomics experiments were performed using the whole heart tissue of the irradiated mice and the control mice not exposed to irradiation. The proteomics data were subjected to bioinformatics analysis, and they indicated that irradiated mouse hearts showed alterations in cardiac fibrosis and energy metabolism proteins. Then, we confirmed the cardiac fibrosis and energy metabolism changes by IHC staining and WB analysis. Extracellular matrix proteins such as Col1a1, Col3a1, Vimentin and CTGF, along with metabolism-related proteins such as Fans and Slc25a1, were overexpressed after exposure to ionizing radiation. Additionally, myocardial mitochondria inner membranes presented with injury, ATP declined and lactic acid accumulated in the irradiated heart tissues. This study suggests that high doses of ionizing radiation lead to structural remodeling, functional injury and fibrosis alterations in the mouse heart. Radiation-induced mitochondrial damage and metabolic alterations of the cardiac tissue may be one of the pathogenic mechanisms of RIHD.