X-irradiation induces acute and early term inflammatory responses in atherosclerosis-prone ApoE(−)/(−) mice and in endothelial cells

Thoracic radiotherapy is an effective treatment for many types of cancer; however it is also associated with an increased risk of developing cardiovascular disease (CVD), appearing mainly ≥10 years after radiation exposure. The present study investigated acute and early term physiological and molecular changes in the cardiovascular system after ionizing radiation exposure. Female and male ApoE(−)/(−) mice received a single exposure of low or high dose X-ray thoracic irradiation (0.1 and 10 Gy). The level of cholesterol and triglycerides, as well as a large panel of inflammatory markers, were analyzed in serum samples obtained at 24 h and 1 month after irradiation. The secretion of inflammatory markers was further verified in vitro in coronary artery and microvascular endothelial cell lines after exposure to low and high dose of ionizing radiation (0.1 and 5 Gy). Local thoracic irradiation of ApoE(−)/(−) mice increased serum growth differentiation factor-15 (GDF-15) and C-X-C motif chemokine ligand 10 (CXCL10) levels in both female and male mice 24 h after high dose irradiation, which were also secreted from coronary artery and microvascular endothelial cells in vitro. Sex-specific responses were observed for triglyceride and cholesterol levels, and some of the assessed inflammatory markers as detailed below. Male ApoE(−)/(−) mice demonstrated elevated intercellular adhesion molecule-1 and P-selectin at 24 h, and adiponectin and plasminogen activator inhibitor-1 at 1 month after irradiation, while female ApoE(−)/(−) mice exhibited decreased monocyte chemoattractant protein-1 and urokinase-type plasminogen activator receptor at 24 h, and basic fibroblast growth factor 1 month after irradiation. The inflammatory responses were mainly significant following high dose irradiation, but certain markers showed significant changes after low dose exposure. The present study revealed that acute/early inflammatory responses occurred after low and high dose thoracic irradiation. However, further research is required to elucidate early asymptomatic changes in the cardiovascular system post thoracic X-irradiation and to investigate whether GDF-15 and CXCL10 could be considered as potential biomarkers for the early detection of CVD risk in thoracic radiotherapy-treated patients.