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Azimzadeh, O. ; Sievert, W. ; Sarioglu, H. ; Merl-Pham, J. ; Yentrapalli, R. ; Bakshi, M.V. ; Janik, D. ; Ueffing, M. ; Atkinson, M.J. ; Multhoff, G. ; Tapio, S.

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)
Verlagsversion Postprint DOI
Open Access Green
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Sprache englisch
Veröffentlichungsjahr 2015
HGF-Berichtsjahr 2015
ISSN (print) / ISBN 1535-3893
e-ISSN 1535-3907
Zeitschrift Journal of Proteome Research
Quellenangaben Band: 14, Heft: 2, Seiten: 1203-1219 Artikelnummer: , Supplement: ,
Verlag American Chemical Society (ACS)
Verlagsort Washington
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Radiation Biology (ISB)
Institute of Pathology (PATH)
CF Metabolomics & Proteomics (CF-MPC)
Institute of Biological and Medical Imaging (IBMI)
Institute of Radiation Medicine (IRM)
POF Topic(s) 30202 - Environmental Health
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30203 - Molecular Targets and Therapies
Forschungsfeld(er) Radiation Sciences
Enabling and Novel Technologies
PSP-Element(e) G-500200-001
G-500300-001
G-505700-001
G-521400-001
G-501390-001
DOI 10.1021/pr501141b
WOS ID WOS:000349276400055
Scopus ID 84922636248
Erfassungsdatum 2015-04-05
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