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

• Published in: Radiotherapy and oncology 2014-04, Vol.111 (1), p.63-71
• Main Authors: Monceau, Virginie, Llach, Anna, Azria, David, Bridier, André, Petit, Benoît, Mazevet, Marianne, Strup-Perrot, Carine, To, Thi-Hong-Van, Calmels, Lucie, Germaini, Marie-Michèle, Gourgou, Sophie, Fenoglietto, Pascal, Bourgier, Céline, Gomez, Ana-Maria, Escoubet, Brigitte, Dörr, Wolfgang, Haagen, Julia, Deutsch, Eric, Morel, Eric, Vozenin, Marie Catherine
• Format: Article
• Language: English
• Subjects: Amyloidosis; Amyloidosis - etiology; Amyloidosis - metabolism; Amyloidosis - pathology; Animals; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - radiotherapy; Calcium - metabolism; Cardiomegaly - etiology; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomyocyte; Epac1; Female; Fibrosis; Fibrosis - etiology; Fibrosis - metabolism; Fibrosis - pathology; Guanine Nucleotide Exchange Factors - metabolism; Heart; Heart - radiation effects; Hematology, Oncology and Palliative Medicine; Humans; Hypertrophy; Life Sciences; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - radiation effects; Radiation Injuries - etiology; Radiation Injuries - metabolism; Radiation Injuries - pathology; Radiotherapy; Rats
• ISSN: 0167-8140; 1879-0887
• DOI: 10.1016/j.radonc.2014.01.025

Abstract 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.