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PPAR Alpha: A Novel Radiation Target in Locally Exposed Mus musculus Heart Revealed by Quantitative Proteomics
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi. (Centre for Radiation Protection Research)
Vise andre og tillknytning
2013 (engelsk)Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 12, nr 6, s. 2700-2714Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Radiation exposure of the thorax is associated with a markedly increased risk of cardiac morbidity and mortality with a latency period of decades. Although many studies have confirmed the damaging effect of ionizing radiation on the myocardium and cardiac endothelial structure and function, the molecular mechanism behind this damage is not yet elucidated. Peroxisome proliferator-activated receptor alpha (PPAR alpha), a transcriptional regulator of lipid metabolism in heart tissue, has recently received great attention in the development of cardiovascular disease. The goal of this study was to investigate radiation-induced cardiac damage in general and the role of PPAR alpha in this process in particular. C57BL/6 mice received local heart irradiation with X-ray doses of 8 and 16 gray (Gy) at the age of 8 weeks. The mice were sacrificed 16 weeks later. Radiation-induced changes in the cardiac proteome were quantified using the Isotope Coded Protein Label (ICPL) method followed by mass spectrometry and software analysis. Significant alterations were observed in proteins involved in lipid metabolism and oxidative phosphorylation. Ionizing radiation markedly changed the phosphorylation and ubiquitination status of PPAR alpha. This was reflected as decreased expression of its target genes involved in energy metabolism and mitochondrial respiratory chain confirming the proteomics data. This study suggests that persistent alteration of cardiac metabolism due to impaired PPAR alpha activity contributes to the heart pathology after radiation.

sted, utgiver, år, opplag, sider
2013. Vol. 12, nr 6, s. 2700-2714
Emneord [en]
ionizing radiation, proteomics, ICPL, PPAR alpha, endothelial cell, heart, cardiovascular disease
HSV kategori
Identifikatorer
URN: urn:nbn:se:su:diva-90482DOI: 10.1021/pr400071gISI: 000320298600032OAI: oai:DiVA.org:su-90482DiVA, id: diva2:625859
Merknad

AuthorCount: 12;

Tilgjengelig fra: 2013-06-05 Laget: 2013-06-05 Sist oppdatert: 2017-12-06bibliografisk kontrollert
Inngår i avhandling
1. Novel radiation targets in the endothelium and heart muscle
Åpne denne publikasjonen i ny fane eller vindu >>Novel radiation targets in the endothelium and heart muscle
2013 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2013. s. 59
Emneord
Ionizing radiation, Endothelial cells, Senescence, Cardiovascular disease, Proteomics
HSV kategori
Forskningsprogram
molekylärgenetik
Identifikatorer
urn:nbn:se:su:diva-90429 (URN)978-91-7447-718-4 (ISBN)
Disputas
2013-10-14, sal E 306, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, Stockholm, 13:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2013-09-22 Laget: 2013-06-04 Sist oppdatert: 2015-04-15bibliografisk kontrollert

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