Abstract 9722: P53-phlda3 Signaling Induced by Carbon-Ion Irradiation is a Novel Therapeutic Target to Suppress Cardiac Hypertrophy in Mice

Background: Irradiation to the heart increases the risk of several cardiac disease including coronary artery disease, heart failure, pericardial disease and cardiac arrythmia, therefore, the heart has been considered one of the organs at risk in thoracic irradiation. On the other hand, recent experimental studies suggested irradiation may ameliorate cardiac injury and arrhythmia after myocardial infarction. To test irradiation effects on pathological cardiac remodeling, we examine the effects from irradiation in a mouse model of heart failure. Methods and Results: We used cardiac hypertrophy and heart failure mice model induced by transverse aortic constriction (TAC), irradiated by X-ray (20, 30 Gy) or carbon-ion beam (10, 30 Gy) at 2 weeks after pressure overload, and examined the changes in cardiac function by echocardiography. Concerning to the X-ray, 1 week after irradiation, ventricular systolic dysfunction induced by TAC was attenuated compared with control group. Among the X-irradiated groups, the higher dose improved cardiac function better. However, at 2 weeks post-irradiation, the cardiac function decreased again. On the other hand, carbon-ion irradiation improved left ventricular function and cardiac hypertrophy even at 2 weeks post-irradiation. The BNP expression was increased in TAC-treated mice and markedly decreased in irradiated mice, suggesting improvement of cardiac hypertrophy and cardiac remodeling. Cardiac p53 phosphorylation is markedly induced by cardiac irradiation. RNA sequencing using irradiated heart revealed pleckstrin homology-like domain family A, member 3 (PHILDA3), a downstream of p53 was significantly upregulated after X-ray or carbon-ion irradiation. PHLDA3 was decreased by TAC treatment, but improved especially in 30 Gy carbon-ion irradiation group. Akt phosphorylation, a hypertrophic signal and downstream target of PHLDA3, was suppressed by irradiation after TAC. Conclusion: Irradiation, especially with carbon-ion beam, brought a beneficial effect on pathological cardiac remodeling. Irradiation induced p53-PHLDA3-Akt signaling might be novel therapeutic target in the pathogenesis of heart failure.