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Radiother Oncol. 2014 Apr;111(1):63-71. doi: 10.1016/j.radonc.2014.01.025. Epub 2014 Apr 7.

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

Author information

1
INSERM U1030, LabEx LERMIT, Villejuif, France; Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre, France.
2
INSERM U769, IFR141, LabEx LERMIT, Faculté de Pharmacie, Châtenay-Malabry, France.
3
Department of Radiation Oncology, CRLC Val d'Aurelle, Montpellier, France.
4
Département de radiothérapie, Institut Gustave Roussy, Villejuif, France.
5
IRSN-PRP-HOM-SRBE-LRTI, Fontenay-aux Roses, France.
6
INSERM U1030, LabEx LERMIT, Villejuif, France; Department of Radiation Oncology, CRLC Val d'Aurelle, Montpellier, France; Département de radiothérapie, Institut Gustave Roussy, Villejuif, France.
7
Département de Physiologie, Explorations Fonctionnelles, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, France; Université Paris Diderot, France; INSERM U872, Paris, France.
8
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.
9
Department of Radiotherapy and Radiation Oncology, Technical University, Dresden, Germany.
10
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.
11
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.

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 (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.

KEYWORDS:

Amyloidosis; Cardiomyocyte; Epac1; Fibrosis; Heart; Hypertrophy; Radiotherapy

PMID:
24721545
DOI:
10.1016/j.radonc.2014.01.025
[Indexed for MEDLINE]
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