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  • 1. Azimzadeh, Omid
    et al.
    Scherthan, Harry
    Yentrapalli, Ramesh
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Barjaktarovic, Zarko
    Ueffing, Marius
    Conrad, Marcus
    Neff, Frauke
    Calzada-Wack, Julia
    Aubele, Michaela
    Buske, Christian
    Atkinson, Michael J.
    Hauck, Stefanie M.
    Tapio, Soile
    Label-free protein profiling of formalin-fixed paraffin-embedded (FFPE) heart tissue reveals immediatemitochondrial impairment after ionising radiation2012In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 75, no 8, p. 2384-2395Article in journal (Refereed)
    Abstract [en]

    Qualitative proteome profiling of formalin-fixed, paraffin-embedded (FFPE) tissue is advancing the field of clinical proteomics. However, quantitative proteome analysis of FFPE tissue is hampered by the lack of an efficient labelling method. The usage of conventional protein labelling on FFPE tissue has turned out to be inefficient. Classical labelling targets lysine residues that are blocked by the formalin treatment. The aim of this study was to establish a quantitative proteomics analysis of FFPE tissue by combining the label-free approach with optimised protein extraction and separation conditions. As a model system we used FFPE heart tissue of control and exposed C57BL/6 mice after total body irradiation using a gamma ray dose of 3 gray. We identified 32 deregulated proteins (p <= 0.05) in irradiated hearts 24 h after the exposure. The proteomics data were further evaluated and validated by bioinformatics and immunoblotting investigation. In good agreement with our previous results using fresh-frozen tissue, the analysis indicated radiation-induced alterations in three main biological pathways: respiratory chain, lipid metabolism and pyruvate metabolism. The label-free approach enables the quantitative measurement of radiation-induced alterations in FFPE tissue and facilitates retrospective biomarker identification using clinical archives.

  • 2. Azimzadeh, Omid
    et al.
    Sievert, Wolfgang
    Sarioglu, Hakan
    Yentrapalli, ramesh
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Barjaktarovic, Zarko
    Sriharshan, Arundhathi
    Ueffing, Marius
    Janik, Dirk
    Aichler, Michaela
    Atkinson, Michael J
    Multhoff, Gabriele
    Tapio, Soile
    PPAR Alpha: A Novel Radiation Target in Locally Exposed Mus musculus Heart Revealed by Quantitative Proteomics2013In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 12, no 6, p. 2700-2714Article in journal (Refereed)
    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.

  • 3.
    Yentrapalli, Ramesh
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology. Helmholtz Zentrum München .
    Azimzadeh, Omid
    Barjaktarovic, Zarko
    Sarioglu, Hakan
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Harms-Ringdahl, Mats
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Atkinson, Michael J.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Tapio, Soile
    Quantitative proteomic analysis reveals induction of premature senescence in human umbilical vein endothelial cells exposed to chronic low-dose rate gamma radiation2013In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 13, no 7, p. 1096-1107Article in journal (Refereed)
    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.

  • 4.
    Yentrapalli, Ramesh
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Helmholtz Zentrum München.
    Azimzadeh, Omid
    Sriharshan, Arundhathi
    Malinowsky, Katharina
    Merl, Juliane
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Harms-Ringdahl, Mats
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Atkinson, Michael J.
    Becker, Karl-Friedrich
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Tapio, Soile
    The PI3K/Akt/mTOR Pathway Is Implicated in the Premature Senescence of Primary Human Endothelial Cells Exposed to Chronic Radiation2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, p. e70024-Article in journal (Refereed)
    Abstract [en]

    The etiology of radiation-induced cardiovascular disease (CVD) after chronic exposure to low doses of ionizing radiation is only marginally understood. We have previously shown that a chronic low-dose rate exposure (4.1 mGy/h) causes human umbilical vein endothelial cells (HUVECs) to prematurely senesce. We now show that a dose rate of 2.4 mGy/h is also able to trigger premature senescence in HUVECs, primarily indicated by a loss of growth potential and the appearance of the senescence-associated markers ß-galactosidase (SA-ß-gal) and p21. In contrast, a lower dose rate of 1.4 mGy/h was not sufficient to inhibit cellular growth or increase SA-ß-gal-staining despite an increased expression of p21. We used reverse phase protein arrays and triplex Isotope Coded Protein Labeling with LC-ESI-MS/MS to study the proteomic changes associated with chronic radiation-induced senescence. Both technologies identified inactivation of the PI3K/Akt/mTOR pathway accompanying premature senescence. In addition, expression of proteins involved in cytoskeletal structure and EIF2 signaling was reduced. Age-related diseases such as CVD have been previously associated with increased endothelial cell senescence. We postulate that a similar endothelial aging may contribute to the increased rate of CVD seen in populations chronically exposed to low-dose-rate radiation.

  • 5.
    Yentrapalli, Venkata Ramesh
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Mechanism behind the development of radiation-induced cardiovascular effects2012Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Epidemiological studies on acutely and chronically exposed individuals indicate that ionising radiation could be a risk factor for cardiovascular diseases. Experimental data regarding radiation-induced cardiovascular late effects are limited and biological mechanisms behind these late effects are still unclear. The estimation of risks concerning low-dose rate and low-dose ionising radiation is still challenging due to lack of experimental evidence.

    The first paper of the thesis describes the radiation-induced protein alterations in cardiac tissue of total body irradiated mice. We use a label-free proteomic approach to identify altered proteins from formalin-fixed paraffin-embedded heart tissue. Comparison between the cardiac proteomes of control and irradiated mice indicates the respiratory chain, lipid metabolism and pyruvate metabolism pathways are affected. We suggest that these biological processes may play a vital role in radiation-induced cardiovascular diseases.

    In the second paper (manuscript) we hypothesized that chronic low-dose rate ionising radiation accelerates premature senescence in endothelial cells and that this may contribute to the radiation-induced cardiovascular diseases. We tested our hypothesis by systematically analysing the growth rate, the number of accumulated senescent cells and the protein expression profiles of the chronically exposed primary human umbilical vein endothelial cells until the cells entered senescence. Decrease in cumulative population doublings and increase in senescent-associated beta-galactosidase stained cells show that chronic exposure to radiation accelerates endothelial cells senescence. Our proteomic results suggest that the cytoskeletal organisation, cell-cell communication and adhesion, inflammation and carbohydrate metabolism were influenced by chronic exposure to radiation. A few deregulated proteins have previously been associated with replicative and stress-induced premature senescence. The results presented here provide new insights on radiation-induced premature senescence in endothelial cells and the changes in protein expression associated with this process.

  • 6.
    Yentrapalli, Venkata Ramesh
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Novel radiation targets in the endothelium and heart muscle2013Doctoral 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.

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