Thoracic radiotherapy increases the risk of radiation-induced heart damage (riHd); however, the molecular mechanisms underlying these changes are not fully understood. The aim of the present study was to investigate the effects of radiation on the mouse heart using high-throughput proteomics. Male c57Bl/6J mice were used to establish a model of riHd by exposing the entire heart to 16 Gy high-energy X-rays, and cardiac injuries were verified using a cardiac echocardiogram, as well as by measuring serum brain natriuretic peptide levels and conducting H&e and Masson staining 5 months after irradiation. Proteomics experiments were performed using the heart apex of 5-month irradiated mice and control mice that underwent sham-irradiation. The most significantly differentially expressed proteins were enriched in 'cardiac fibrosis' and 'energy metabolism'. Next, the cardiac fibrosis and changes to energy metabolism were confirmed using immunohistochemistry staining and western blotting. extracellular matrix proteins, such as collagen type 1 α 1 chain, collagen type iii α 1 chain, vimentin and cccTc-binding factor, along with metabolism-related proteins, such as fatty acid synthase and solute carrier family 25 member 1, exhibited upregulated expression following exposure to ionizing radiation. additionally, the myocardial mitochondria inner membranes were injured, along with a decrease in aTP levels and the accumulation of lactic acid in the irradiated heart tissues. These results suggest that the high doses of ionizing radiation used lead to structural remodeling, functional injury and fibrotic alterations in the mouse heart. Radiation-induced mitochondrial damage and metabolic alterations of the cardiac tissue may thus be a pathogenic mechanism of riHd.

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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.