Modulation of gene expression in endothelial cells in response to high LET nickel ion irradiation

Abstract

Abstract. Ionizing radiation can elicit harmful effects on the cardiovascular system at high doses. Endothelial cells are critical targets in radiation-induced cardiovascular damage. Astronauts performing a long-term deep space mission are exposed to consistently higher fluences of ionizing radiation that may accumulate to reach high effective doses. In addition, cosmic radiation contains high linear energy transfer (LET) radiation that is known to produce high values of relative biological effectiveness (RBE). The aim of this study was to broaden the understanding of the molecular response to high LET radiation by investigating the changes in gene expression in endothelial cells. For this purpose, a human endothelial cell line (EA.hy926) was irradiated with accelerated nickel ions (Ni) (LET, 183 keV/ µm) at doses of 0.5, 2 and 5 Gy. DNA damage was measured 2 and 24 h following irradiation by γ-H2AX foci detection by fluorescence microscopy and gene expression changes were measured by microarrays at 8 and 24 h following irradiation. We found that exposure to accelerated nickel particles induced a persistent DNA damage response up to 24 h after treatment. This was accompanied by a downregulation in the expression of a multitude of genes involved in the regulation of the cell cycle and an upregulation in the expression of genes involved in cell cycle checkpoints. In addition, genes involved in DNA damage response, oxidative stress, apoptosis and cell-cell signaling (cytokines) were found to be upregulated. An in silico analysis of the involved genes suggested that the transcription factors, E2F and nuclear factor (NF)-κB, may be involved in these cellular responses.

Research Progress on Signaling Pathway‐Associated Oxidative Stress in Endothelial Cells

“…NF- κ B can promote apoptosis in endothelial cells when endothelium is subjected to irradiation such as ultraviolet B (UVB) and hadron; this action is based on the upregulation of tumor necrosis factor alpha (TNF- α ) and is significantly enhanced upon costimulation with interleukin-1 (IL-1) and IL-6 [27]. Apart from UVB radiation, NF- κ B is also commonly activated by oxidants such as H 2 O 2 .…”

Molecular Signaling in Response to Charged Particle Exposures and its Importance in Particle Therapy

“…After 56 Fe-ion exposure, p53 and genes controlling apoptosis were upregulated [79]. In the human endothelial cell line EA.hy926, 58 Ni-ion (LET 183 keV/lm) exposure induced expression of genes involved in endothelial permeability and apoptosis signaling [80].…”

Invited Review Article: Advanced light microscopy for biological space research

“…[6][7][8] Space experiments and ground-based simulations have also shown that both factors induce marked changes in gene expression. [9][10][11] Despite these documented relationships, major uncertainties remain regarding the exact contribution of IR and μg to human disorders and the underlying molecular and cellular mechanisms. For instance, it is not clear to what extent HZE-induced DNA damage or μg-induced cytoskeletal reorganizations persist upon prolonged exposure, if and how physical or biochemical communication between cells and within a multi-cellular organism contributes to the response, or how both factors jointly affect spatiotemporal gene expression patterns, differentiation and development.…”

“…Both adherent (e.g., carcinoma cells and fibroblasts) and suspension cells (e.g., lymphocytes), primary and transformed, have been used in space and ground-based experiments to study the complex influence of a reduced gravitational force on mammalian cell growth and function, including effects on gene expression 9,10,28 and cytoskeletal organization 29,30 as well as the effects of cosmic radiation on DNA damage repair 5,11 and cytokine secretion. 5,31 Nevertheless, most cellbased studies are being performed with individual cells, either in suspension, or as adherent monolayers cultured on hard, flat surfaces.…”