ABSTRACT
AIMS: Microvascular endothelial cell dysfunction is a leading cause of radiation-induced heart disease (RIHD). BRCA1 plays an important role in DNA damage repair. The study aims to explore the effect of BRCA1 in endothelial cells involved in RIHD. MATERIALS AND METHODS: BRCA1 and p21 expression were detected in human umbilical vein endothelial cells (HUVECs) and in mouse heart tissue after irradiation exposure. The effects of BRCA1 on cell proliferation, cell cycle and radiosensitivity were determined in HUVECs with overexpression and knockdown of BRCA1. A mouse model of RIHD was established. Heart damage was detected in C57BL/6J mice and endothelial cell specific knockout BRCA1 mice (EC-BRCA1-/-). KEY FINDINGS: BRCA1 and p21 expression was significantly increased both in vitro and vivo response to irradiation. BRCA1 overexpression in endothelial cells enhanced cell growth and G1/S phase arrest, and the opposite results were observed in BRCA1 knockdown endothelial cells. BRCA1 downregulated endothelial cell cycle-related genes cyclin A, cyclin D1, cyclin E and p-Rb through increasing p21 expression, and HUVECs with BRCA1 gene knockdown were more sensitive to radiation. In vivo, a decrease in cardiac microvascular density, as well as cardiomyocyte hypoxia and apoptosis were observed in a time-dependent manner. EC-BRCA1-/- mice were more prone to severe RIHD than EC-BRCA1+/- mice after 16Gy radiation exposure due to endothelial dysfunction caused by loss of BRCA1, and p21 was declined in EC-BRCA1-/- mice heart. SIGNIFICANCE: These findings indicate that BRCA1 plays a protective role in RIHD by regulating endothelial cell cycle arrest mediated by p21 signal.
Subject(s)
BRCA1 Protein/metabolism , Cell Cycle Checkpoints , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Human Umbilical Vein Endothelial Cells/cytology , Neovascularization, Pathologic/prevention & control , Protective Agents/administration & dosage , Radiation Tolerance , Animals , BRCA1 Protein/genetics , BRCA1 Protein/physiology , Cell Proliferation , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p21/genetics , Human Umbilical Vein Endothelial Cells/metabolism , Human Umbilical Vein Endothelial Cells/radiation effects , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neovascularization, Pathologic/etiology , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Radiation, IonizingABSTRACT
BACKGROUND: Early screening and diagnosis of radiation-induced heart disease (RIHD) is difficult in patients with chest radiation exposure. sST-2 is involved in myocardial stress or injury. We evaluated the relationship between heart dose parameters and sST-2 changes in chest malignant tumor patients who received chest radiation. METHODS: We prospectively collected thoracic malignancy cancer patients who had received chest radiotherapy. Heart dosimetry parameters were extracted from the treatment planning system. sST-2 was measured at baseline, the middle stage, and after radiotherapy (recorded as pre-ST-2, mid-ST-2, and post-ST-2). sST-2 change rate was calculated. Scatter plots showed the relationship between cardiac dose parameters and ST-2 change rate. Multiple regression was used to analyze the relationship between cardiac dose parameters and ST-2 change rate. RESULTS: Totally, 60 patients were enrolled. The mean V5 , V10 , V20 , V30 , V40 , and MHD was 60.93 ± 27.79%, 51.43 ± 25.44%, 39.17 ± 21.75%, 28.07 ± 17.15%,18.66 ± 12.18%, and 18.60 ± 8.63 Gy, respectively. The median M-LAD was 11.31 (IQR 3.33-18.76) Gy. The mean pre-ST-2, mid-ST-2, and post-ST-2 was 5.1 ± 3.8, 6.4 ± 3.9, and 7.6 ± 4.4, respectively. sST-2 was elevated with thoracic irradiation (P < .001). Multivariate linear regression analyses showed that V5 , V10 , V20 , and MHD were independently and positively associated with ST-2 change rate (ß = .04, .04, .04, and .10, respectively, all P < .05). CONCLUSION: Serum sST-2 levels were elevated over time during radiotherapy. V5 , V10 , V20 and MHD were independently and positively associated with the elevated ST-2 change rate.
