The anti-angiogenesis role of FBXW7 in diabetic retinopathy by facilitating the ubiquitination degradation of c-Myc to orchestrate the HDAC2.
The anti-angiogenesis role of FBXW7 in diabetic retinopathy by facilitating the ubiquitination degradation of c-Myc to orchestrate the HDAC2.
复制标题
FBXW 7在糖尿病视网膜病变中的抗血管生成作用是通过促进c-Myc的泛素化降解来协调HDAC 2。
DOI：
10.1111/jcmm.16204
复制
发表时间：
2021-03
影响因子：
5.3
通讯作者：
Hu J
中科院分区：
文献类型：
--
作者：
Hu L;Lv X;Li D;Zhang W;Ran G;Li Q;Hu J
糖尿病视网膜病变（DR）是糖尿病患者中最常见的微血管并发症，可引起严重的视力损害。FBXW7在乳腺癌中具有抗血管生成作用。因此，本研究旨在揭示FBXW7在DR血管生成中的作用机制，采用高糖高脂饮食诱导小鼠DR模型，并采用高糖高脂饮食诱导正常小鼠视网膜微血管内皮细胞（RMECs），通过免疫荧光、免疫组织化学或Western blot分析FBXW7、Ki67、HIF - 1α和VEGF的表达。在对正常小鼠和DR小鼠进行功能获得和功能丧失实验后，通过CD31荧光染色和Western blot分析评估血管生成。在HG诱导的RMEC异位表达和沉默实验后，分别用EdU、Transwell和体外血管生成法检测RMEC的增殖、迁移和血管生成。通过环己亚胺追踪实验和蛋白酶体抑制实验研究了FBXW7对c‐Myc泛素化的影响，并通过双荧光素酶报告基因实验研究了c‐Myc与HDAC2启动子的结合。DR小鼠和HG诱导的RMECs具有下调的FBXW7和上调的Ki67、HIF - 1α和VEGF。沉默FBXW7增强了正常小鼠视网膜组织的血管生成，但过表达FBXW7或沉默c‐Myc会抑制DR小鼠视网膜组织的血管生成。过表达FBXW7或沉默c - Myc可抑制HG诱导的rmec的增殖、迁移和血管生成。FBXW7诱导c - Myc泛素化降解，c - Myc通过结合HDAC2启动子增强HDAC2表达。最后，我们的数据为FBXW7通过调节c - Myc/HDAC2轴在DR中的抗血管生成作用提供了新的视角。
Diabetic retinopathy (DR) is the most prevalently occurring microvascular complication in diabetic patients that triggers severe visual impairments. The anti‐angiogenesis role of FBXW7 has been identified in breast cancer. Therefore, this study intends to decipher the mechanism of FBXW7 in angiogenesis of DR. DR model was induced on mice using high‐glucose (HG) and high‐fat diet, and retinal microvascular endothelial cells (RMECs) isolated from normal mice were induced with HG, followed by evaluation of FBXW7, Ki67, HIF‐1α and VEGF expression by immunofluorescence, immunohistochemistry or Western blot analysis. After gain‐ and loss‐of‐function assays in normal and DR mice, angiogenesis was assessed by CD31 fluorescence staining and Western blot analysis. After ectopic expression and silencing experiments in HG‐induced RMECs, RMEC proliferation, migration and angiogenesis were, respectively, determined by EdU, Transwell and in vitro angiogenesis assays. The impact of FBXW7 on the ubiquitination of c‐Myc was studied by cycloheximide chase assay and proteasome inhibition, and the binding of c‐Myc to HDAC2 promoter by dual‐luciferase reporter gene experiment. DR mice and HG‐induced RMECs possessed down‐regulated FBXW7 and up‐regulated Ki67, HIF‐1α and VEGF. Silencing FBXW7 enhanced angiogenesis in normal mouse retinal tissue, but overexpressing FBXW7 or silencing c‐Myc diminished angiogenesis in DR mouse retinal tissue. Overexpressing FBXW7 or silencing c‐Myc depressed proliferation, migration and angiogenesis in HG‐induced RMECs. FBXW7 induced c‐Myc ubiquitination degradation, and c‐Myc augmented HDAC2 expression by binding to HDAC2 promoter. Conclusively, our data provided a novel sight of anti‐angiogenesis role of FBXW7 in DR by modulating the c‐Myc/HDAC2 axis.
登录
查看更多内容
影响因子：
5.6
作者：
Bolinger MT;Antonetti DA
通讯作者：
Antonetti DA
影响因子：
4.2
作者：
Inanc, Merve;Tekin, Kemal;Aycan, Zehra
通讯作者：
Aycan, Zehra
影响因子：
4.1
作者：
Shao, Jun;Fan, Guangming;Yao, Yong
通讯作者：
Yao, Yong
影响因子：
6.4
作者：
Park, Jee Young;Kim, Pil-Jong;Go, Heounjeong
通讯作者：
Go, Heounjeong
影响因子：
4
作者：
Guan, Liuliu;Zou, Qingqing;Chen, Size
通讯作者：
Chen, Size