Department of Cardiology and Cardiovascular Disease Research Institute, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
Department of Cardiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
Environ Toxicol. 2023 Dec;38(12):2952-2966. doi: 10.1002/tox.23930. Epub 2023 Aug 24.
Circular RNAs (circRNAs), a new subgroup of non-coding RNAs in the human transcriptome, are crucial in atherosclerosis (AS). Here, a newly identified circRNA circDLGAP4 was demonstrated to be downregulated in oxidized forms of low-density lipoprotein (ox-LDL)-induced HUVECs.
This research adopted ox-LDL to stimulate human umbilical vein endothelial cells (HUVECs) to mimic AS in vitro. To further validate the protective action of circDLGAP4 in AS, a mouse model of AS was constructed with a high-fat diet. Functional assays evaluated circDLGAP4 role in AS in vitro and in vivo. Moreover, mechanism assays evaluated association of circDLGAP4/miR-134-5p/PTPN4.
CircDLGAP4 was induced to promote cell proliferative behavior and autophagy, inhibit apoptotic and inflammatory activities in ox-LDL-treated HUVECs, and attenuated endothelial barrier function. CircDLGAP4 regulated PTPN4 by directly targeting miR-134-5p. Meanwhile, inhibiting miR-134-5p reduced ox-LDL-induced cell dysfunction. Knockout of PTPN4 reversed circDLGAP4 overexpression or miR-134-5p downregulation in vitro. In addition, reducing circDLGAP4 or overexpressing miR-134-5p increased the red atherosclerotic plaque and lesion area of AS mice, reduced autophagy level, and promoted the release of inflammatory cytokines.
This study extends the role of circRNA in AS by inducing autophagy and improving endothelial dysfunction in AS via the circDLGAP4/miR-134-5p/PTPN4 axis.
环状 RNA（circRNAs）是人类转录组中非编码 RNA 的一个新亚群，在动脉粥样硬化（AS）中具有重要作用。在这里，研究人员证实了一种新鉴定的环状 RNA circDLGAP4 在氧化型低密度脂蛋白（ox-LDL）诱导的人脐静脉内皮细胞（HUVEC）中表达下调。
本研究采用 ox-LDL 刺激人脐静脉内皮细胞（HUVEC），在体外模拟 AS。为了进一步验证 circDLGAP4 在 AS 中的保护作用，构建了高脂饮食诱导的 AS 小鼠模型。功能测定评估了 circDLGAP4 在体外和体内 AS 中的作用。此外，机制测定评估了 circDLGAP4/miR-134-5p/PTPN4 的关联。
CircDLGAP4 被诱导促进 ox-LDL 处理的 HUVEC 中的细胞增殖行为和自噬，抑制凋亡和炎症活性，并减弱内皮屏障功能。CircDLGAP4 通过直接靶向 miR-134-5p 调节 PTPN4。同时，抑制 miR-134-5p 可减少 ox-LDL 诱导的细胞功能障碍。在体外，敲除 PTPN4 逆转了 circDLGAP4 过表达或 miR-134-5p 下调。此外，降低 circDLGAP4 或过表达 miR-134-5p 增加了 AS 小鼠的红色动脉粥样硬化斑块和病变面积，降低了自噬水平，并促进了炎症细胞因子的释放。
本研究通过 circDLGAP4/miR-134-5p/PTPN4 轴诱导自噬并改善 AS 中的内皮功能障碍，扩展了 circRNA 在 AS 中的作用。
