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Quantitative proteomic analysis reveals induction of premature senescence in human umbilical vein endothelial cells exposed to chronic low-dose rate gamma radiation
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology. Helmholtz Zentrum München .
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2013 (English)In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 13, no 7, 1096-1107 p.Article in journal (Refereed) Published
Abstract [en]

Chronic low-dose ionizing radiation induces cardiovascular disease in human populations but the mechanism is largely unknown. We suggested that chronic radiation exposure may induce endothelial cell senescence that is associated with vascular damage in vivo. We investigated whether chronic radiation exposure is causing a change in the onset of senescence in endothelial cells in vitro. Indeed, when exposed to continuous low-dose rate gamma radiation (4.1 mGy/h), primary human umbilical vein endothelial cells (HUVECs) initiated senescence much earlier than the nonirradiated control cells. We investigated the changes in the protein expression of HUVECs before and during the onset of radiation-induced senescence. Cellular proteins were quantified using isotope-coded protein label technology after 1, 3, and 6 weeks of radiation exposure. Several senescence-related biological pathways were influenced by radiation, including cytoskeletal organization, cellcell communication and adhesion, and inflammation. Immunoblot analysis showed an activation of the p53/p21 pathway corresponding to the progressing senescence. Our data suggest that chronic radiation-induced DNA damage and oxidative stress result in induction of p53/p21 pathway that inhibits the replicative potential of HUVECs and leads to premature senescence. This study contributes to the understanding of the increased risk of cardiovascular diseases seen in populations exposed to chronic low-dose irradiation.

Place, publisher, year, edition, pages
2013. Vol. 13, no 7, 1096-1107 p.
Keyword [en]
Cell biology, Endothelium, ICPL, Ionizing radiation, Senescence
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:su:diva-89869DOI: 10.1002/pmic.201200463ISI: 000317290000006OAI: diva2:621305


Available from: 2013-05-14 Created: 2013-05-14 Last updated: 2013-09-05Bibliographically approved
In thesis
1. Novel radiation targets in the endothelium and heart muscle
Open this publication in new window or tab >>Novel radiation targets in the endothelium and heart muscle
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Worldwide, people are being exposed to natural and man-made sources of radiation. Epidemiological studies have shown an increased risk of vascular diseases in populations that have been exposed to ionizing radiation. Vascular endothelium is implicated as one of the targets for radiation leading to the development of cardiovascular diseases. However, the molecular mechanisms behind the development of radiation-induced cardiovascular disease in acute or chronic exposed people are not fully elucidated. The hypothesis that chronic low dose rate ionizing radiation accelerates the onset of senescence of primary human umbilical vein endothelial cells has been tested in papers I and II presented in this thesis. In vitro studies show that, when exposed to continuous low dose rate gamma radiation these cells enter premature senescence much earlier than non-irradiated control cells. Quantitative proteomic analysis using isotope coded protein labeling coupled to LC-ESI-mass spectrometry and followed by protein network analysis identified changes in senescence-related biological pathways including cytoskeletal organisation, cell-cell communication and adhesion, and inflammation influenced by radiation. Moreover, the role of PI3K/Akt/mTOR pathway was implicated during the senescence process. Thus, chronic low dose rated endothelial senescence may contribute to increased risk of radiation-induced cardiovascular disease.

Paper III analyse the long-term effects of local high doses of radiation to the heart using a mouse model. The results from proteomic and bioinformatics analysis indicated that an impaired activity of the peroxisome proliferator-activated receptor-alpha (PPARA) is involved in mediating the radiation response. Ionizing radiation markedly changed the phosphorylation and ubiquitination status of PPARA. This was reflected by the decreased expression of PPARA target genes involved in energy metabolism and mitochondrial respiratory chain. This in vivo study suggests that alteration of cardiac metabolism contributes to the impairment of heart structure and function after radiation.

Taken together, these in vitro and in vivo studies provide novel information on the pathways in heart and endothelial cells that are affected over longer periods of time by ionizing radiation.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2013. 59 p.
Ionizing radiation, Endothelial cells, Senescence, Cardiovascular disease, Proteomics
National Category
Biological Sciences
Research subject
Molecular Genetics
urn:nbn:se:su:diva-90429 (URN)978-91-7447-718-4 (ISBN)
Public defence
2013-10-14, sal E 306, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, Stockholm, 13:00 (English)
Available from: 2013-09-22 Created: 2013-06-04 Last updated: 2015-04-15Bibliographically approved

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Yentrapalli, RameshWojcik, AndrzejHarms-Ringdahl, MatsHaghdoost, Siamak
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