Fenofibrate attenuates the adverse effects of radiation on endothelial cells through modulation of ROS-NO signalling and inflammation

Exposure to high doses of ionizing radiation has been consistently associated with the development of cardiovascular disease (CVD), particularly in patients undergoing thoracic radiotherapy. Radiation-induced CVD is characterized by alterations in metabolic and inflammatory homeostasis in the heart and vascular system. These changes promote myocardial and vascular pathological remodelling. Over time, such changes contribute to the development of atherosclerosis and heart failure. A key driver of these alterations is inactivation of the transcription factor peroxisome proliferator-activated receptor alpha (PPARα). Activation of PPARα by its agonist, fenofibrate, has shown to reduce the irradiation effects on the cardiac proteome of mice. However, the molecular effects of fenofibrate on individual cell types, including vascular endothelial cells, are unknown. To assess the potential effects of fenofibrate on irradiated vascular endothelium, we performed label-free proteomic analysis of human coronary artery endothelial cells treated with fenofibrate (10 μM) or DMSO at 2- and 7-days post-irradiation (4 Gy). The alterations in expression level and activity status of crucial proteins and mRNA contributing to the affected pathways were further validated. Fenofibrate effectively restored critical molecular and cellular processes disrupted by irradiation, including cell survival, oxidative stress response, ROS production, PI3K-AKT-eNOS signalling, NO bioavailability, inflammatory responses via interferon signalling and endothelial-to-mesenchymal transition. Taken together, these findings further highlight the involvement of PPARα in modulating the cardiovascular response to radiation exposure. Accordingly, the results suggest that administering fenofibrate may have a benefit in preventing vascular disease after radiation exposure. Preventing or mitigating endothelial injury, and inflammation represents a key strategy to preserve vascular integrity and improving long-term cardiovascular outcomes in cancer survivors following radiotherapy.