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Abstract
Purpose: Epidemiological studies indicate that radiation doses as low as 0.5 Gy increase the risk of cardiovascular disease decades after the exposure. The aim of the present study was to investigate whether this radiation dose causes late molecular alterations in endothelial cells that could support the population-based data.
Materials and methods: Human coronary artery endothelial cells were irradiated at 0.5 Gy (X-ray) and radiation-induced changes in the proteome were investigated after different time intervals (1, 7 and 14 d) using ICPL technology. Key changes identified by proteomics and bioinformatics were validated by immunoblotting and ELISA.
Results: The radiation-induced alteration of the endothelial proteome was characterized by sustained perturbation of Rho GDP-dissociation inhibitor (RhoGDI) and nitric oxide (NO) signalling pathways. At later time-points, this was accompanied by reduced proteasome activity, enhanced protein carbonylation indicating augmented oxidative stress, and senescence.
Conclusions: These molecular changes are indicative of long-term premature endothelial dysfunction and provide a mechanistic framework to the epidemiological data showing increased risk of cardiovascular disease at 0.5 Gy.
Acknowledgements
We thank Stefanie Winkler and Sandra Helm for excellent technical assistance. This work was supported by a grant from the European Community’s Seventh Framework Program (EURATOM), Contract no. 295823 (PROCARDIO).
Disclosure statement
No potential conflict of interest was reported by the authors.
Notes on contributors
Omid Azimzadeh, PhD, is a research scientist in the group of Radiation Proteomics at the Institute of Radiation Biology at HMGU. His research interests focus on the effects of radiation exposure on normal tissue with a specific emphasis on the myocardial and endothelial proteome response.
Vikram Subramanian is a PhD student at HMGU. His thesis investigates the role of PPAR alpha in radiation-induced heart disease.
Susanne Ständer was a master student at HMGU and currently a PhD at the Max Planck Institute of Biochemistry, Martinsried. Her master topic was the proteomic response of irradiated endothelium.
Juliane Merl-Pham, PhD, is a group leader in the Research Unit Protein Science at HMGU, with a research focus on proteomic signatures in barrier diseases. Further, she is responsible for project management and quality controlled LC-MS/MS measurements in the Core Facility Proteomics at HMGU.
Donna Lowe has been researching radiation effects at Public Health England (formerly Health Protection Agency) since 2006 and is currently undertaking a PhD investigating cellular effects of chronic radiation exposure at the University of Cambridge.
Zarko Barjaktarovic, PhD, is a research scientist in the group of Radiation Proteomics at the Institute of Radiation Biology at HMGU. He investigates radiation-induced post-translational protein modifications.
Simone Moertl, PhD, is a group leader at the Institute for Radiation Biology at HMGU with key interests in the role of short non coding RNAs and extracellular vesicles in radiation response of tumour and normal tissue.
Ken Raj, PhD, is a group leader at Public Health England with research interest in mechanisms of radiation effects, cardiovascular disease and ageing.
Michael J. Atkinson, PhD, is the director of the Institute of Radiation Biology at the Helmholtz Zentrum München and Chair of Radiation Biology at the Technical University of Munich. His research goal is the improvement of radiation therapy by modulating the actions of radiation on tumour cells and non-cancerous tissues.
Soile Tapio, PhD, leads the group of Radiation Proteomics at the Institute of Radiation Biology at HMGU. Her research topic is radiation-induced normal tissue damage in heart and brain.