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Integrative proteomics and targeted transcriptomics analyses in cardiac endothelial cells unravel mechanisms of long-term radiation-induced vascular dysfunction.
J. Proteome Res. 14, 1203-1219 (2015)
Epidemiological data from radiotherapy patients show the damaging effect of ionizing radiation on heart and vasculature. The endothelium is the main target of radiation damage and contributes essentially to the development of cardiac injury. However, the molecular mechanisms behind the radiation-induced endothelial dysfunction are not fully understood. In the present study, 10-week-old C57Bl/6 mice received local X-ray heart doses of 8 or 16 Gy and were sacrificed after 16 weeks; the controls were sham-irradiated. The cardiac microvascular endothelial cells were isolated from the heart tissue using streptavidin-CD31-coated microbeads. The cells were lysed and proteins were labeled with duplex isotope-coded protein label methodology for quantification. All samples were analyzed by LC–ESI–MS/MS and Proteome Discoverer software. The proteomics data were further studied by bioinformatics tools and validated by targeted transcriptomics, immunoblotting, immunohistochemistry, and serum profiling. Radiation-induced endothelial dysfunction was characterized by impaired energy metabolism and perturbation of the insulin/IGF-PI3K-Akt signaling pathway. The data also strongly suggested premature endothelial senescence, increased oxidative stress, decreased NO availability, and enhanced inflammation as main causes of radiation-induced long-term vascular dysfunction. Detailed data on molecular mechanisms of radiation-induced vascular injury as compiled here are essential in developing radiotherapy strategies that minimize cardiovascular complications.
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Publication type Article: Journal article
Document type Scientific Article
Keywords ionizing radiation; proteomics; ICPL; insulin; PI3K; PPAR alpha; endothelial cell; endothelial cell dysfunction; heart; cardiovascular disease; Activated Receptor-alpha; Nitric-oxide Synthase; Insulin-resistance; Oxidative Stress; Cardiovascular-disease; Heart-disease; Ppar-alpha; Coronary Atherosclerosis; Premature Senescence; Glut4 Translocation
ISSN (print) / ISBN 1535-3893
Journal Journal of Proteome Research
Quellenangaben Volume: 14, Issue: 2, Pages: 1203-1219
Publisher American Chemical Society (ACS)
Publishing Place Washington
Reviewing status Peer reviewed