Pituitary adenylate cyclase-activating polypeptide ameliorates radiation-induced cardiac injury

Radiation-induced heart disease (RIHD) is a common sequelae of thoracic irradiation. Currently, there is no effective prevention and treatment strategy. Oxidative stress is associated with the development of RIHD. Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) has been defined as the multipotent properties of cytoprotective effect on its anti-apoptotic and antioxidant activities. Here, we set to investigate whether PACAP38 plays a role in attenuating RIHD. We established radiation-related cardiac injury models using 6MV X-ray based on H9C2 cardiomyocytes and male C57/BL6 mice which were pre-treated with PACAP38 prior to radiation exposure. PACAP38 protected mice from radiation-induced histological damage including myocardial apoptosis and fibrosis. Also, cell viability and colony-forming efficiency were enhanced and intracellular ROS generation was reduced in PACAP38 treated H9C2 cardiomyocytes exposed to radiation. Moreover, PACAP38 suppressed myocardial apoptosis and G2/M arrest through blunting the radiation-induced down-regulation of Bcl-2, CyclinB1 and CDC2, and inhibiting the up-regulation of Bax. Furthermore, irradiation resulted in activating of NRF2 and HO-1 expressions were further enhanced by PACAP38 in H9C2 cells and the protective effect of PACAP38 was partially blocked by NRF2 siRNA silencing. In summary, PACAP38 has the potential to effectively protect against acute radiation-induced cardiac injury and its cardioprotective effect involves upregulation of NRF2/HO-1-dependent signaling activation.