Journal
RADIOTHERAPY AND ONCOLOGY
Volume 111, Issue 1, Pages 63-71Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.radonc.2014.01.025
Keywords
Radiotherapy; Epac1; Cardiomyocyte; Heart; Hypertrophy; Amyloidosis; Fibrosis
Funding
- ARC - European Commission [FP7-Fission-2007-3.1.1]
- CARDIORISK - European Commission [FP7-Fission-2007-3.1.1]
- FRM Grant (Programme Physiopathologie Cardiovasculaire)
- ANR [Geno-09-Carythm, ANR-10-LABX-33]
- LabEx Lermit - ANR Grant
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Background: Cardiac toxicity is a side-effect of anti-cancer treatment including radiotherapy and this translational study was initiated to characterize radiation-induced cardiac side effects in a population of breast cancer patients and in experimental models in order to identify novel therapeutic target. Methods: The size of the heart was evaluated in CO-HO-RT patients by measuring the Cardiac-Contact-Distance before and after radiotherapy (48 months of follow-up). In parallel, fibrogenic signals were studied in a severe case of human radiation-induced pericarditis. Lastly, radiation-induced cardiac damage was studied in mice and in rat neonatal cardiac cardiomyocytes. Results: In patients, time dependent enhancement of the CCD was measured suggesting occurrence of cardiac hypertrophy. In the case of human radiation-induced pericarditis, we measured the activation of fibrogenic (CTGF, RhoA) and remodeling (MMP2) signals. In irradiated mice, we documented decreased contractile function, enlargement of the ventricular cavity and long-term modification of the time constant of decay of Ca2+ transients. Both hypertrophy and amyloid deposition were correlated with the induction of Epac-1; whereas radiation-induced fibrosis correlated with Rho/CTGF activation. Transactivation studies support Epac contribution in hypertrophy stimulation and showed that radiotherapy and Epac displayed specific and synergistic signals. Conclusion: Epac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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