Application of radiation omics in the development of adverse outcome pathway networks: an example of radiation-induced cardiovascular disease

Azimzadeh, Omid; Moertl, Simone; Ramadan, Raghda; Baselet, Bjorn; Laiakis, Evagelia C.; Sebastian, Soji; Beaton, Danielle; Hartikainen, Jaana M.; Kaiser, Jan Christian; Beheshti, Afshin; Salomaa, Sisko; Chauhan, Vinita; Hamada, Nobuyuki

doi:10.1080/09553002.2022.2110325

Cited by 16 publications

(9 citation statements)

References 252 publications

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“…Other overlapping pathways between the rat DMRs (current study) and proteomics dataset [19] include cardiac muscle contraction, hypertrophic cardiomyopathy, adrenergic signaling in cardiomyocytes and longevity regulating pathway (DMRs at 1.5 months), as well as gonadotropin releasing hormone (GnRH) secretion, dopaminergic synapse, tight junction and circadian entrainment (DMRs at 7 months). All of these pathways have been previously implicated in cardiovascular impairment [47][48][49][50][51][52][53][54][55][56]. Dysregulation of these pathways has been known to result from oxidative stress, a proven contributor in radiation-induced cardiotoxicity [50,[57][58][59][60][61][62].…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Alterations in Fractionally Irradiated Rats and Breast Cancer Patients Receiving Radiotherapy

Sallam

Mysara

Benotmane

et al. 2022

IJMS

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Radiation-Induced CardioVascular Disease (RICVD) is an important concern in thoracic radiotherapy with complex underlying pathophysiology. Recently, we proposed DNA methylation as a possible mechanism contributing to RICVD. The current study investigates DNA methylation in heart-irradiated rats and radiotherapy-treated breast cancer (BC) patients. Rats received fractionated whole heart X-irradiation (0, 0.92, 6.9 and 27.6 Gy total doses) and blood was collected after 1.5, 3, 7 and 12 months. Global and gene-specific methylation of the samples were evaluated; and gene expression of selected differentially methylated regions (DMRs) was validated in rat and BC patient blood. In rats receiving an absorbed dose of 27.6 Gy, DNA methylation alterations were detected up to 7 months with differential expression of cardiac-relevant DMRs. Of those, SLMAP showed increased expression at 1.5 months, which correlated with hypomethylation. Furthermore, E2F6 inversely correlated with a decreased global longitudinal strain. In BC patients, E2F6 and SLMAP exhibited differential expression directly and 6 months after radiotherapy, respectively. This study describes a systemic radiation fingerprint at the DNA methylation level, elucidating a possible association of DNA methylation to RICVD pathophysiology, to be validated in future mechanistic studies.

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Section: Discussionmentioning

confidence: 99%

DNA Methylation Alterations in Fractionally Irradiated Rats and Breast Cancer Patients Receiving Radiotherapy

Sallam

Mysara

Benotmane

et al. 2022

IJMS

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“…A study by Schöllnberger et al (83,84) did not definitively establish a risk of heart disease for individuals exposed to doses below 2.6 Gy, while Azizova et al ( 85) indicated an increased risk of developing ischemic heart disease for cumulative external doses above 1 Gy. However, there is a lack of epidemiological data on the impact of radiation on cardiovascular diseases after exposure to low to moderate doses, particularly below 500 mGy (86)(87)(88)(89)(90)(91)(92)(93). Several experimental studies have focused on investigating the effects of low-dose radiation using mouse models of atherosclerosis, specifically genetically modified ApoE knocked out (KO) mice fed a chow diet.…”

Section: Discussionmentioning

confidence: 99%

Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition

Nguyen,

Imanishi,

et al. 2023

Front. Cardiovasc. Med.

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BackgroundThe deSUMOylase sentrin-specific isopeptidase 2 (SENP2) plays a crucial role in atheroprotection. However, the phosphorylation of SENP2 at T368 under disturbed flow (D-flow) conditions hinders its nuclear function and promotes endothelial cell (EC) activation. SUMOylation has been implicated in D-flow-induced endothelial-to-mesenchymal transition (endoMT), but the precise role of SENP2 in counteracting this process remains unclear.MethodWe developed a phospho-specific SENP2 S344 antibody and generated knock-in (KI) mice with a phospho-site mutation of SENP2 S344A using CRISPR/Cas9 technology. We then investigated the effects of SENP2 S344 phosphorylation under two distinct flow patterns and during hypercholesteremia (HC)-mediated EC activation.ResultOur findings demonstrate that laminar flow (L-flow) induces phosphorylation of SENP2 at S344 through the activation of checkpoint kinase 1 (CHK1), leading to the inhibition of ERK5 and p53 SUMOylation and subsequent suppression of EC activation. We observed a significant increase in lipid-laden lesions in both the aortic arch (under D-flow) and descending aorta (under L-flow) of female hypercholesterolemic SENP2 S344A KI mice. In male hypercholesterolemic SENP2 S344A KI mice, larger lipid-laden lesions were only observed in the aortic arch area, suggesting a weaker HC-mediated atherogenesis in male mice compared to females. Ionizing radiation (IR) reduced CHK1 expression and SENP2 S344 phosphorylation, attenuating the pro-atherosclerotic effects observed in female SENP2 S344A KI mice after bone marrow transplantation (BMT), particularly in L-flow areas. The phospho-site mutation SENP2 S344A upregulates processes associated with EC activation, including inflammation, migration, and proliferation. Additionally, fibrotic changes and up-regulated expression of EC marker genes were observed. Apoptosis was augmented in ECs derived from the lungs of SENP2 S344A KI mice, primarily through the inhibition of ERK5-mediated expression of DNA damage-induced apoptosis suppressor (DDIAS).SummaryIn this study, we have revealed a novel mechanism underlying the suppressive effects of L-flow on EC inflammation, migration, proliferation, apoptosis, and fibrotic changes through promoting CHK1-induced SENP2 S344 phosphorylation. The phospho-site mutation SENP2 S344A responds to L-flow through a distinct mechanism, which involves the upregulation of both mesenchymal and EC marker genes.

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“…The use of the AOP conceptual framework for radiation exposure was proposed in the early 2010s (258) and has been extensively discussed since then. So far, hypothetical AOPs have been developed for several noncancer effects, e.g., for DCS (259)(260)(261), microcephaly (262), renal toxicity (263) and reproductive effects (264), and an international horizonstyle exercise was conducted to gauge the level of awareness, interest, hesitation and even barriers in implementing the AOP framework in radiation research and regulation (265). ICRP, MELODI, NASEM, NCRP, OECD/NEA and UNSCEAR have all regarded the AOP approach as important to improve radiation protection (218-220, 247, 266).…”

Section: Integration Of Epidemiology and Biologymentioning

confidence: 99%

Noncancer Effects of Ionizing Radiation Exposure on the Eye, the Circulatory System and beyond: Developments made since the 2011 ICRP Statement on Tissue Reactions

Hamada

2023

Radiation Research

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For radiation protection purposes, noncancer effects with a threshold-type dose-response relationship have been classified as tissue reactions (formerly called nonstochastic or deterministic effects), and equivalent dose limits aim to prevent occurrence of such tissue reactions. Accumulating evidence demonstrates increased risks for several late occurring noncancer effects at doses and dose rates much lower than previously considered. In 2011, the International Commission on Radiological Protection (ICRP) issued a statement on tissue reactions to recommend a threshold of 0.5 Gy to the lens of the eye for cataracts and to the heart and brain for diseases of the circulatory system (DCS), independent of dose rate. Literature published thereafter continues to provide updated knowledge. Increased risks for cataracts below 0.5 Gy have been reported in several cohorts (e.g., including in those receiving protracted or chronic exposures). A dose threshold for cataracts is less evident with longer follow-up, with limited evidence available for risk of cataract removal surgery. There is emerging evidence for risk of normal-tension glaucoma and diabetic retinopathy, but the long-held tenet that the lens represents among the most radiosensitive tissues in the eye and in the body seems to remain unchanged. For DCS, increased risks have been reported in various cohorts, but the existence or otherwise of a dose threshold is unclear. The level of risk is less uncertain at lower dose and lower dose rate, with the possibility that risk per unit dose is greater at lower doses and dose rates. Target organs and tissues for DCS are also unknown, but may include heart, large blood vessels and kidneys. Identification of potential factors (e.g., sex, age, lifestyle factors, coexposures, comorbidities, genetics and epigenetics) that may modify radiation risk of cataracts and DCS would be important. Other noncancer effects on the radar include neurological effects (e.g., Parkinsonŉs disease and dementia) of which elevated risk has increasingly been reported. These late occurring noncancer effects tend to deviate from the definition of tissue reactions, necessitating more scientific developments to reconsider the radiation effect classification system and risk management. This paper gives an overview of historical developments made in ICRP prior to the 2011 statement and an update on relevant developments made since the 2011 ICRP statement.

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Application of radiation omics in the development of adverse outcome pathway networks: an example of radiation-induced cardiovascular disease

Cited by 16 publications

References 252 publications

DNA Methylation Alterations in Fractionally Irradiated Rats and Breast Cancer Patients Receiving Radiotherapy

DNA Methylation Alterations in Fractionally Irradiated Rats and Breast Cancer Patients Receiving Radiotherapy

Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition

Noncancer Effects of Ionizing Radiation Exposure on the Eye, the Circulatory System and beyond: Developments made since the 2011 ICRP Statement on Tissue Reactions

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