Local heart irradiation of ApoE−/− mice induces microvascular and endocardial damage and accelerates coronary atherosclerosis

Gabriels, Karen; Hoving, Saske; Seemann, Ingar; Visser, Nils L.; Gijbels, Marion J.J.; Pol, Jeffrey F.; Daemen, Mat J.A.P.; Stewart, Fiona; Heeneman, Sylvia

doi:10.1016/j.radonc.2012.08.002

Cited by 73 publications

(49 citation statements)

References 26 publications

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“…In a prospective study, 8 patients underwent additional ultrasound, MRI and myocardial SPECT to investigate 38 papers matching pubmed criteria 38 9 papers were excluded because of Russian, German or Japanese language 29 22 papers were excluded because they adressed radiotherapy planning issues (18), case reports (2), other toxiciƟes (1) punblished before 1980(1) 7 6 papers were included screening references from selected papers 13 13 papers were considered relevant [13]. Patients were subjected to cardiac MRIs before, during and shortly after therapy.…”

Section: Resultsmentioning

confidence: 99%

Is cardiac toxicity a relevant issue in the radiation treatment of esophageal cancer?

Beukema

Luijk²,

Widder

et al. 2015

Radiotherapy and Oncology

128

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Section: Resultsmentioning

confidence: 99%

Is cardiac toxicity a relevant issue in the radiation treatment of esophageal cancer?

Beukema

Luijk²,

Widder

et al. 2015

Radiotherapy and Oncology

128

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“…Work over recent years has shown that irradiation of the heart during treatment for breast cancer leads to long-term increased risk for atherosclerotic coronary disease (12). However, this dose-dependent pathology evolves over the long term and is not replicated in mice unless they are also predisposed to atherosclerosis, as in mice with ApoE deficiency (13), and so might not emerge in some model systems.…”

Section: The Role Of Atm In Damage Responsementioning

confidence: 99%

Radiation and ATM inhibition: the heart of the matter

Hammond¹,

Muschel²

2014

J. Clin. Invest.

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C o m m e n t a r y 3 2 8 9 jci.org Volume 124 Number 8 August 2014Radiation and ATM inhibition: the heart of the matter The role of ATM in damage responseThe ataxia telangiectasia mutated (ATM) kinase is a member of the PI3K-like protein kinase (PIKK) family with extensive roles in DNA damage response signaling (reviewed in ref. 1). In addition, ATM can respond to non-DNA-damaging stresses and has recently been described as having a role in neoangiogenesis in a melanoma model (2-5). DNA damage leads to activation of ATM kinase activity and thus phosphorylation of a myriad of downstream targets, including p53, CHK2, and KAP-1 (6, 7). This activation triggers cell cycle checkpoints, arrest, and delays in the G 1 , S, and G 2 phases of the cell cycle and enables DNA repair of double-stranded breaks both by homologous recombination and by nonhomologous end joining (8, 9). Hence, fibroblasts and tumor cells are radiosensitized to X-ray radiation therapy (XRT) in culture by pharmacological ATM inhibition, or by ATM mutation and deletion (10). These data suggest that inhibition of ATM should radiosensitize tumors; however, there is a hesitancy to employ this strategy clinically, due to fears that normal tissues could be substantially sensitized as well. This reluctance is well founded, as it is based on the catastrophic response of patients with ataxia telangiectasia (AT) to XRT. The AT syndrome, which is now characterized in part by extreme radiosensitivity, is caused by mutations in the ATM gene. Before AT was fully characterized, a few patients who developed lymphoma (a frequent event in AT) were radiated to treat mediastinal cancers and suffered drastic side effects. Those few reports stressed severe mucositis of the esophagus and skin desquamation (e.g., ref.11). This led to the subsequently proven supposition that ATM plays an important role in the response and repair of DNA damage, but also the understandable reticence of clinicians to consider XRT for AT patients and reluctance to use AT inhibitors because of the potential normal tissue sensitivity. While the clinical observations point to mucous membranes and skin as targets for deleterious normal tissue effects, it should be remembered that thoracic radiation also inevitably results in some radiation dose to the heart. Work over recent years has shown that irradiation of the heart during treatment for breast cancer leads to long-term increased risk for atherosclerotic coronary disease (12). However, this dose-dependent pathology evolves over the long term and is not replicated in mice unless they are also predisposed to atherosclerosis, as in mice with ApoE deficiency (13), and so might not emerge in some model systems. An elegant model to understand the role of ATMIn this issue, Moding et al. used an innovative and intricate system to distinguish the effects of ATM deletion in endothelium from the heart and from tumors (14). The authors used a sarcoma model that they previously established in mice with mutant Kras G12D and p53 flanked by inactivating stop ...

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“…This leads to permeability 328 and vasomotor changes in endothelial cells and induces leucocyte 329 trafficking [103,104]. In an experimental mouse model of cardiac 330 irradiation, endothelial damage was seen at doses of 2 Gy; and a 331 decrease in alkaline phosphatase activity in the myocardial 332 endothelial cells at 20 and 40 weeks after exposure [105]. 333 3.2.3.…”

Section: Studymentioning

confidence: 99%

Low-dose ionising radiation and cardiovascular diseases – Strategies for molecular epidemiological studies in Europe

Kreuzer

Auvinen

Cardis

et al. 2015

Mutation Research/Reviews in Mutation Research

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Local heart irradiation of ApoE−/− mice induces microvascular and endocardial damage and accelerates coronary atherosclerosis

Cited by 73 publications

References 26 publications

Is cardiac toxicity a relevant issue in the radiation treatment of esophageal cancer?

Is cardiac toxicity a relevant issue in the radiation treatment of esophageal cancer?

Radiation and ATM inhibition: the heart of the matter

Low-dose ionising radiation and cardiovascular diseases – Strategies for molecular epidemiological studies in Europe

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