Life sciences (1973), 2020-03, Vol.244, p.117342-117342, Article 117342
2020
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- BRCA1 protects cardiac microvascular endothelial cells against irradiation by regulating p21-mediated cell cycle arrest
- Ist Teil von
- Life sciences (1973), 2020-03, Vol.244, p.117342-117342, Article 117342
- Ort / Verlag
- Netherlands: Elsevier Inc
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. 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−/−). 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. These findings indicate that BRCA1 plays a protective role in RIHD by regulating endothelial cell cycle arrest mediated by p21 signal. Graphical abstract of the findings. BRCA1 plays a protective role in radiation-induced heart disease by regulating vessel endothelial cell cycle arrest mediated by p21 signaling pathway. Abbreviation: CMECs, cardiac microvascular endothelial cells; RIHD, radiation-induced heart disease. [Display omitted] •BRCA1 plays a protective role in radiation-induced heart disease.•Endothelial cell BRCA1-/- knockout mice were more prone to severe Radiation-related heart disease (RIHD).•BRCA1 in cardiac endothelial cells plays a role in the response to radiation by regulating p21-cell cycle arrest.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0024-3205eISSN: 1879-0631DOI: 10.1016/j.lfs.2020.117342Titel-ID: cdi_proquest_miscellaneous_2345505734
- Format
- –
- Schlagworte
- Animal tissues, Animals, Apoptosis, BRCA1, BRCA1 protein, BRCA1 Protein - genetics, BRCA1 Protein - metabolism, BRCA1 Protein - physiology, Breast cancer, Cardiomyocytes, Cardiovascular diseases, Cell cycle, Cell Cycle Checkpoints, Cell growth, Cell Proliferation, Cells, Cultured, Coronary artery disease, Cyclin A, Cyclin D1, Cyclin E, Cyclin-dependent kinase inhibitor p21, Cyclin-Dependent Kinase Inhibitor p21 - genetics, Cyclin-Dependent Kinase Inhibitor p21 - metabolism, Damage detection, Deoxyribonucleic acid, DNA, DNA damage, DNA repair, EC-BRCA1−/− mice, Endothelial cells, Exposure, Gene expression, Heart, Heart diseases, Human Umbilical Vein Endothelial Cells - cytology, Human Umbilical Vein Endothelial Cells - metabolism, Human Umbilical Vein Endothelial Cells - radiation effects, Humans, Hypoxia, Irradiation, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microvascular damage, Microvasculature, Neovascularization, Pathologic - etiology, Neovascularization, Pathologic - metabolism, Neovascularization, Pathologic - pathology, Neovascularization, Pathologic - prevention & control, Nitric oxide, p21, Protective Agents - administration & dosage, Radiation, Radiation damage, Radiation effects, Radiation induced heart disease, Radiation Tolerance, Radiation, Ionizing, Radiosensitivity, S phase, Time dependence, Umbilical vein