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


CONCLUSIONS
Epac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart.
INSERM U1030, LabEx LERMIT, Villejuif, France; Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre, France.
Virginie
V
Monceau
INSERM U769, IFR141, LabEx LERMIT, Faculté de Pharmacie, Châtenay-Malabry, France.
Anna
A
Llach
Department of Radiation Oncology, CRLC Val d'Aurelle, Montpellier, France.
David
D
Azria
Département de radiothérapie, Institut Gustave Roussy, Villejuif, France.
André
A
Bridier
INSERM U1030, LabEx LERMIT, Villejuif, France; Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre, France.
Benoît
B
Petit
INSERM U769, IFR141, LabEx LERMIT, Faculté de Pharmacie, Châtenay-Malabry, France.
Marianne
M
Mazevet
IRSN-PRP-HOM-SRBE-LRTI, Fontenay-aux Roses, France.
Carine
C
Strup-Perrot
INSERM U1030, LabEx LERMIT, Villejuif, France; Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre, France.
Thi-Hong-Van
TH
To
Département de radiothérapie, Institut Gustave Roussy, Villejuif, France.
Lucie
L
Calmels
INSERM U769, IFR141, LabEx LERMIT, Faculté de Pharmacie, Châtenay-Malabry, France.
Marie-Michèle
MM
Germaini
Department of Radiation Oncology, CRLC Val d'Aurelle, Montpellier, France.
Sophie
S
Gourgou
Department of Radiation Oncology, CRLC Val d'Aurelle, Montpellier, France.
Pascal
P
Fenoglietto
INSERM U1030, LabEx LERMIT, Villejuif, France; Department of Radiation Oncology, CRLC Val d'Aurelle, Montpellier, France; Département de radiothérapie, Institut Gustave Roussy, Villejuif, France.
Céline
C
Bourgier
INSERM U769, IFR141, LabEx LERMIT, Faculté de Pharmacie, Châtenay-Malabry, France.
Ana-Maria
AM
Gomez
Département de Physiologie, Explorations Fonctionnelles, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, France; Université Paris Diderot, France; INSERM U872, Paris, France.
Brigitte
B
Escoubet
Department of Radiotherapy and Radiation Oncology, Technical University, Dresden, Germany; Department of Radiation Oncology & Christian Doppler Laboratory for Medical Radiation Research in Radiooncology Medical University, Vienna, Austria.
Wolfgang
W
Dörr
Department of Radiotherapy and Radiation Oncology, Technical University, Dresden, Germany.
Julia
J
Haagen
INSERM U1030, LabEx LERMIT, Villejuif, France; Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre, France; Département de radiothérapie, Institut Gustave Roussy, Villejuif, France.
Eric
E
Deutsch
INSERM U769, IFR141, LabEx LERMIT, Faculté de Pharmacie, Châtenay-Malabry, France.
Eric
E
Morel
INSERM U1030, LabEx LERMIT, Villejuif, France; Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre, France; Laboratoire de Radio-oncologie, CHUV, Lausanne, Switzerland. Electronic address: Marie-Catherine.vozenin@chuv.ch.
Marie Catherine
MC
Vozenin
D000686:Amyloidosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006321:Heart / Q000528:radiation effects*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000528:radiation effects; D011832:Radiation Injuries / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051381:Rats
D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D002118:Calcium
Amyloidosis; Cardiomyocyte; Epac1; Fibrosis; Heart; Hypertrophy; Radiotherapy