TY - JOUR
T1 - Epac contributes to cardiac hypertrophy and amyloidosis induced by radiotherapy but not fibrosis
AU - Monceau, Virginie
AU - Llach, Anna
AU - Azria, David
AU - Bridier, André
AU - Petit, Benoît
AU - Mazevet, Marianne
AU - Strup-Perrot, Carine
AU - To, Thi Hong Van
AU - Calmels, Lucie
AU - Germaini, Marie Michèle
AU - Gourgou, Sophie
AU - Fenoglietto, Pascal
AU - Bourgier, Céline
AU - Gomez, Ana Maria
AU - Escoubet, Brigitte
AU - Dörr, Wolfgang
AU - Haagen, Julia
AU - Deutsch, Eric
AU - Morel, Eric
AU - Vozenin, Marie Catherine
N1 - Funding Information:
This work was supported by ARC and CARDIORISK which was an Integrated Project funded by the European Commission (FP7-Fission-2007-3.1.1), by a FRM Grant (Programme Physiopathologie Cardiovasculaire 2011), ANR (Geno-09-Carythm), and the LabEx Lermit (funded by an ANR Grant). VM and MM are fellows of the LabeX Lermit. VT is a fellow from Université Paris-Sud 11. AL is a fellow from Fondation Lefoulon de Lalande Lefoulon. We thank Olivia Bawa for excellent technical assistance in histology, IGR-SCEA for animal care. We thank the Department of LIPA for the use of ultrasonographic system (Aplio, Toshiba). Inserm U1030 and Inserm U769 are members of the Laboratory of Excellence LERMIT supported by a Grant from ANR (ANR-10-LABX-33).
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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.
AB - 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.
KW - Amyloidosis
KW - Cardiomyocyte
KW - Epac1
KW - Fibrosis
KW - Heart
KW - Hypertrophy
KW - Radiotherapy
UR - http://www.scopus.com/inward/record.url?scp=84902147971&partnerID=8YFLogxK
U2 - 10.1016/j.radonc.2014.01.025
DO - 10.1016/j.radonc.2014.01.025
M3 - Article
C2 - 24721545
AN - SCOPUS:84902147971
SN - 0167-8140
VL - 111
SP - 63
EP - 71
JO - Radiotherapy and Oncology
JF - Radiotherapy and Oncology
IS - 1
ER -