BRCA1 protects cardiac microvascular endothelial cells against irradiation by regulating p21-mediated cell cycle arrest.
BRCA1 protects cardiac microvascular endothelial cells against irradiation by regulating p21-mediated cell cycle arrest.
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DOI：
10.1016/j.lfs.2020.117342
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发表时间：
2020-01
期刊：
影响因子：
6.1
通讯作者：
Z. Zeng;H. Du;Le Xiong;Xiaoli Zeng;Peng Zhang;Jing Cai;Long Huang;Anwen Liu
中科院分区：
文献类型：
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作者：
Z. Zeng;H. Du;Le Xiong;Xiaoli Zeng;Peng Zhang;Jing Cai;Long Huang;Anwen Liu
微血管内皮细胞功能障碍是放射性心脏病（RIHD）的主要原因。BRCA 1在DNA损伤修复中起重要作用。为探讨BRCA 1在放射性心脏病血管内皮细胞中的作用，采用放射性心脏病血管内皮细胞模型，检测放射性心脏病血管内皮细胞（HUVECs）和小鼠心脏组织中BRCA 1和p21的表达。BRCA 1对HUVECs细胞增殖、细胞周期和放射敏感性的影响在BRCA 1过表达和敲低的HUVECs中测定。建立RIHD小鼠模型。在C57 BL/6 J小鼠和内皮细胞特异性敲除BRCA 1小鼠（EC-BRCA 1 −/−）中检测到心脏损伤。关键发现BRCA 1和p21表达在体外和体内对辐射的反应中都显著增加。内皮细胞中BRCA 1过表达促进细胞生长和G1/S期阻滞，而BRCA 1敲低内皮细胞中观察到相反的结果。BRCA 1通过增加p21表达下调内皮细胞周期相关基因cyclin A、cyclin D1、cyclin E和p-Rb，BRCA 1基因敲低的HUVECs对辐射更敏感。在体内，心脏微血管密度的减少，以及心肌细胞缺氧和凋亡，观察到的时间依赖性的方式。EC-BRCA 1 −/−小鼠在16 Gy照射后比EC-BRCA 1 +/−小鼠更容易发生严重的RIHD，这是由于BRCA 1缺失导致的内皮功能障碍，并且EC-BRCA 1 −/−小鼠心脏中p21水平下降。
AimsMicrovascular 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 methodsBRCA1 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 findingsBRCA1 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.SignificanceThese findings indicate that BRCA1 plays a protective role in RIHD by regulating endothelial cell cycle arrest mediated by p21 signal.