CircDLGAP4 induces autophagy and improves endothelial cell dysfunction in atherosclerosis by targeting PTPN4 with miR-134-5p.

Abstract

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.