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Epac contributes to cardiac hypertrophy and amyloidosis induced by radiotherapy but not fibrosis.

Authors: Monceau, V  Llach, A  Azria, D  Bridier, A  Petit, B  Mazevet, M  Strup-Perrot, C  To, TH  Calmels, L  Germaini, MM  Gourgou, S  Fenoglietto, P  Bourgier, C  Gomez, AM  Escoubet, B  Dorr, W  Haagen, J  Deutsch, E  Morel, E  Vozenin, MC 
Citation: Monceau V, etal., Radiother Oncol. 2014 Apr;111(1):63-71. doi: 10.1016/j.radonc.2014.01.025. Epub 2014 Apr 7.
Pubmed: (View Article at PubMed) PMID:24721545
DOI: Full-text: DOI:10.1016/j.radonc.2014.01.025

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 (48months 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 Ca(2+) 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.

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CRRD Object Information
CRRD ID: 9835365
Created: 2015-03-19
Species: All species
Last Modified: 2015-03-19
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.