Differential Impact of Single-Dose Fe Ion and X-Ray Irradiation on Endothelial Cell Transcriptomic and Proteomic Responses

Baselet, Bjorn; Azimzadeh, Omid; Erbeldinger, N.; Bakshi, Mayur V.; Dettmering, T.; Janssen, Ann; Ktitareva, Svetlana; Lowe, Donna; Michaux, Arlette; Quintens, Roel; Raj, Kenneth; Durante, Marco; Fournier, Claudia; Benotmane, Mohammed Abderrafi; Baatout, Sarah; Sonveaux, Pierre; Tapio, Soile; Aerts, An

doi:10.3389/fphar.2017.00570

Cited by 19 publications

(17 citation statements)

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“…Endothelial inflammation and adhesiveness increased with x-rays (250 kV) but decreased after 56 Fe-ion exposure (155 keV/lm). Moreover, 2-Gy x-rays and iron ions both enhanced the expression of proteins involved in caveolar-mediated endocytosis signaling and cell-cell adhesion [79]. After x-irradiation, genes involved in cell-cycle control were upregulated, whereas cell-adhesion genes were downregulated.…”

Section: Cardiovascular Systemmentioning

confidence: 98%

“…Both helium-ion (LET 76 keV/lm) and x-ray (250 kV) exposure (0.1-2 Gy) of human microvascular endothelial cells decreased TNF-a-induced leukocyte adhesion to endothelial cells under laminar conditions [78]. Baselet et al [79] compared differences in signaling after exposure of endothelial cells from human coronary arteries to x-rays and 56 Fe ions (LET 155 keV/lm). Endothelial inflammation and adhesiveness increased with x-rays (250 kV) but decreased after 56 Fe-ion exposure (155 keV/lm).…”

Section: Cardiovascular Systemmentioning

confidence: 99%

“…After x-irradiation, genes involved in cell-cycle control were upregulated, whereas cell-adhesion genes were downregulated. 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].…”

Section: Cardiovascular Systemmentioning

confidence: 99%

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

Hellweg

Chishti

Diegeler

et al. 2018

International Journal of Particle Therapy

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Energetic, charged particles elicit an orchestrated DNA damage response (DDR) during their traversal through healthy tissues and tumors. Complex DNA damage formation, after exposure to high linear energy transfer (LET) charged particles, results in DNA repair foci formation, which begins within seconds. More protein modifications occur after high-LET, compared with low-LET, irradiation. Charged-particle exposure activates several transcription factors that are cytoprotective or cytodestructive, or that upregulate cytokine and chemokine expression, and are involved in bystander signaling. Molecular signaling for a survival or death decision in different tumor types and healthy tissues should be studied as prerequisite for shaping sensitizing and protective strategies. Long-term signaling and gene expression changes were found in various tissues of animals exposed to charged particles, and elucidation of their role in chronic and late effects of charged-particle therapy will help to develop effective preventive measures.A major difference between low-LET and high-LET radiation is the microscopic dose deposition. Charged particles deposit their energy along densely ionized tracks [5]. In chromosomes within those tracks, complex damage is produced, defined as 2 or more abasic sites, oxidized bases on opposing strands or the same strand, and strand breaks on opposite DNA strands within a few helical turns ( Figure 1) [5][6][7][8][9][10][11][12]. That damage is difficult to repair and affects rejoining faithfulness [13][14][15]. DNA repair systems have an intrinsic weakness in processing complex damages [16]. Molecular signaling in response to charged-particle exposure is predominantly a DNA damage response (DDR), turning the switch toward cellular survival or death ( Figure 2).Ionizing radiation activates phosphatidylinositol-3-kinase-related enzymes, including ataxia telangiectasia mutant (ATM), ataxia telangiectasia, Rad3-related protein (ATR), and DNA-dependent protein kinase (DNA-PK) [21]. The ATM and ATR are recruited to complex double-strand breaks (DSBs) (Figure 3) [22].Mutations in ATM cause radiation hypersensitivity in patients with the autosomal recessive disorder ataxia-telangiectasia [16]. Mice with ATM haploinsufficiency develop cataracts earlier compared with wild-type animals, and the enhanced sensitivity was greater for high-LET heavy ions compared with low-LET x-rays [23].There are 4 autophosphorylation sites in ATM: Ser-367, Ser-1893, Ser-1981, and Ser-2996. Ser-1981 phosphorylation is associated with ATM monomerization. In human fibroblasts, ATM phosphorylated at Ser-367 is recruited to DNA damage sites after exposure to xenon ions (LET 800 keV/lm) [24]. Very early events include phosphorylation of the histone variant H2AX on Ser-139 (cH2AX) by ATM [25]. That results in protein recruitment to the DNA lesions, forming foci in LET-dependent kinetics [26]. The fast-recruited proteins are responsible for damage recognition, and slower accumulating proteins are predominantly involved in subsequent repai...

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Section: Cardiovascular Systemmentioning

confidence: 98%

Section: Cardiovascular Systemmentioning

confidence: 99%

Section: Cardiovascular Systemmentioning

confidence: 99%

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

Hellweg

Chishti

Diegeler

et al. 2018

International Journal of Particle Therapy

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“…This is a significant and pressing issue as stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) modalities have become mainstream in radiation oncology. Through computer‐aided field shaping and careful treatment planning, dosimetry and improved radiation delivery systems, X‐ray doses as high as 20 Gy in a single fraction and 60 Gy in 3–5 fractions are delivered in contemporary SBRT and SRS, and the therapeutic mechanisms associated to such high doses as well as their effects on the microvasculature remain controversial . Conversely, studies have highlighted profound radiation quality‐dependent radiobiological differences between X‐ray and high LET particle therapies.…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, studies have highlighted profound radiation quality‐dependent radiobiological differences between X‐ray and high LET particle therapies. For example, the endothelial cell response to radiation was found to be more pronounced and longer lasting for Fe ions than for X‐rays . C‐ions were also reported to induce more acute damages to endothelial cells than X‐rays…”

Section: Introductionmentioning

confidence: 99%

Validation of a Vasculogenesis Microfluidic Model for Radiobiological Studies of the Human Microvasculature

Guo

Yang

Maritz

et al. 2019

Adv Materials Technologies

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The therapeutic ratio of radiotherapy is limited by acute or chronic side effects with often severe consequences to patients. The microvasculature is a central player involved in both tumor responses and healthy tissue/organ radiological injuries. However, current preclinical vascular models based on 2D culture offer only limited radiobiological insight due to their failure in recapitulating the 3D nature experienced by endothelial cells within the human microvasculature. To address this issue, the use of a 3D microvasculature‐on‐a‐chip microfluidic technology is demonstrated in radiobiological studies. Within this vasculogenesis model a perfusable network that structurally mimics the human microvasculature is formed and the biological response to ionizing radiation including cellular apoptosis, vessel tight adherens junction breakage, DNA double strand break, and repair is systematically investigated. In comparison to cells grown in a 2D environment, human umbilical vein endothelial cells in the 3D microvasculature‐on‐a‐chip displays significant differences in biological responses, especially at high X‐ray dose. This data confirms the feasibility of using microvascular‐on‐a‐chip models for radiobiological studies. Such vasculogenesis models have strong potential to yield more accurate prediction of healthy tissue responses to ionizing radiation as well as to guide the development of risk‐reducing strategies to prevent radiation‐induced acute and long‐term side‐effects.

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Pathological effects of ionizing radiation: endothelial activation and dysfunction

Baselet

Sonveaux

Baatout

et al. 2018

Cell. Mol. Life Sci.

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195

141

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The endothelium, a tissue that forms a single layer of cells lining various organs and cavities of the body, especially the heart and blood as well as lymphatic vessels, plays a complex role in vascular biology. It contributes to key aspects of vascular homeostasis and is also involved in pathophysiological processes, such as thrombosis, inflammation, and hypertension. Epidemiological data show that high doses of ionizing radiation lead to cardiovascular disease over time. The aim of this review is to summarize the current knowledge on endothelial cell activation and dysfunction after ionizing radiation exposure as a central feature preceding the development of cardiovascular diseases.

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Differential Impact of Single-Dose Fe Ion and X-Ray Irradiation on Endothelial Cell Transcriptomic and Proteomic Responses

Cited by 19 publications

References 84 publications

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

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

Validation of a Vasculogenesis Microfluidic Model for Radiobiological Studies of the Human Microvasculature

Pathological effects of ionizing radiation: endothelial activation and dysfunction

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