Study on the Mechanism of Autophagy in Rats With Radiation Induced Heart Damage at Different Time Points

Abstract

It is an important mode to combine local radiotherapy with systemic targeted therapy against tumor. MTOR is an ideal choice for tumor targeted therapy, which has been identified in the cardiovascular disease. Endoplasmic reticulum stress (ERS) was involved in the process of radiation induced heart damage (RIHD) in previous study, which could trigger autophagy by inhibiting mTOR. Here we established an animal experimental model to observe the performance of RIHD at different time points, and explored the mechanism of autophagy in a rat model of RIHD.56 adult male SD rats were randomly divided into four groups (n = 14): Control group (A), Radiation group (B), Rapamycin+radiation group (C), 3-MA + radiation Group (D). Animal echocardiography was performed on the 14th and 28th days after irradiation to record left ventricular function. Levels of IL-4, TNF-α, TGF-β1 and Beclin-1 and LC3 related to autophagy were assessed by quantitative analysis of protein expression.1. On the 14th day after irradiation, radiation exposure caused a decrease in LVFS, and the decrease was recovered in D group but was not changed in C group. On the 28th day after irradiation, radiation exposure caused an increase in LVEF and LVFS, accompanied by LVAW; s thickening, and except for the decrease of LVAW; s in C group there was no change of the other parameters in C and D group compared with B group. 2. On the 14th day after the heart of the rat is irradiated, edema of myocardial cells and apoptosis increased, myocardial interstitial and perivascular inflammation cells infiltrated, and myocardial interstitial collagen deposition increased. The above-mentioned injuries were aggravated in C group and were alleviated in D group compared with B group. With time extending to 28 days after irradiation, the above-mentioned histopathological changes were progressively exacerbated. Different from changes of the 14th day, these damages were alleviated in C group and were aggravated in D group on the 28th day. 3. On the 14th day, irradiation increased the levels of autophagy-related proteins Beclin-1 and LC3, inflammatory factors IL-4, TNF-α and TGF-β1. Enhancing autophagy furtherly increased the levels of inflammatory factors IL-4, TNF-α and TGF-β1. On the 28th day, irradiation reduced the expression of Beclin-1 and LC3 but still increased the levels of IL-4, TNF-α and TGF-β1. Enhancing autophagy decreased the levels of inflammatory factors IL-4, TNF-α and TGF-β1.RIHD were progressively exacerbated with the extension of observation time. Autophagy may play a bidirectional regulatory role in radiation- induced cardiac injury, and the mechanism of action is different at different time points. On the 14th day after irradiation, activated autophagy exacerbated acute radiation heart injury to a certain extent. As time prolonged to 28 days after irradiation, down-regulated autophagy exacerbated acute radiation heart injury to a certain extent.