Enhanced sensitivity to low dose irradiation of ApoE-/- mice mediated by early pro-inflammatory profile and delayed activation of the TGFβ1 cascade involved in fibrogenesis

Investigating long-term cardiac effects of low doses of ionizing radiation is highly relevant in the context of interventional cardiology and radiotherapy. Epidemiological data report that low doses of irradiation to the heart can result in significant increase in the cardiovascular mortality by yet...

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Published in:	PloS one 2013-02, Vol.8 (2), p.e57052-e57052
Main Authors:	Monceau, Virginie, Meziani, Lydia, Strup-Perrot, Carine, Morel, Eric, Schmidt, Magret, Haagen, Julia, Escoubet, Brigitte, Dörr, Wolfgang, Vozenin, Marie-Catherine
Format:	Article
Language:	eng
Subjects:	Animals Apolipoprotein E Apolipoproteins E - genetics Apolipoproteins E - physiology Arteriosclerosis Atherosclerosis Biology Blotting, Western Breast cancer Cardiology Cardiomyocytes Cardiovascular disease Cardiovascular diseases Complications Dose-Response Relationship, Radiation Echocardiography Epidemiology Fibrosis Heart Heart attacks Heart diseases Heart failure Hypertension Hypertrophy Infiltration Inflammation Inflammation Mediators - blood Interleukin 6 Ionizing radiation Irradiated Irradiation Laboratories Macrophages Male Medicine Mice Mice, Inbred C57BL Mice, Knockout Morbidity Mortality Muridae Oncology Polyamide-imides Post-irradiation Radiation Radiation damage Radiation dosage Radiation effects Radiation therapy Scars Sensitivity enhancement Transforming Growth Factor beta1 - metabolism Transforming growth factor-b1 Ventricle
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Summary:	Investigating long-term cardiac effects of low doses of ionizing radiation is highly relevant in the context of interventional cardiology and radiotherapy. Epidemiological data report that low doses of irradiation to the heart can result in significant increase in the cardiovascular mortality by yet unknown mechanisms. In addition co-morbidity factor such as hypertension or/and atherosclerosis can enhance cardiac complications. Therefore, we explored the mechanisms that lead to long-term cardiac remodelling and investigated the interaction of radiation-induced damage to heart and cardiovascular systems with atherosclerosis, using wild-type and ApoE-deficient mice. ApoE-/- and wild-type mice were locally irradiated to the heart at 0, 0.2 and 2 Gy (RX). Twenty, 40 and 60 weeks post-irradiation, echocardiography were performed and hearts were collected for cardiomyocyte isolation, histopathological analysis, study of inflammatory infiltration and fibrosis deposition. Common and strain-specific pathogenic pathways were found. Significant alteration of left ventricular function (eccentric hypertrophy) occurred in both strains of mice. Low dose irradiation (0.2 Gy) induced premature death in ApoE-/- mice (47% died at 20 weeks). Acute inflammatory infiltrate was observed in scarring areas with accumulation of M1-macrophages and secretion of IL-6. Increased expression of the fibrogenic factors (TGF-β1 and PAI-1) was measured earlier in cardiomyocytes isolated from ApoE-/- than in wt animals. The present study shows that cardiac exposure to low dose of ionizing radiation induce significant physiological, histopathological, cellular and molecular alterations in irradiated heart with mild functional impairment. Atherosclerotic predisposition precipitated cardiac damage induced by low doses with an early pro-inflammatory polarization of macrophages.
ISSN:	1932-6203 1932-6203