Circular RNA circ_0026218 Suppressed Atherosclerosis Progression via miR-338-3p/SIRT6 Axis

Abstract

Background. Multiple circular RNAs (circRNAs) are implicated in atherosclerosis (AS) pathogenesis. In fact, how circRNA 0026218 (circ_0026218) functions in AS remains unknown, and thus the functions and mechanisms of circ_0026218 in the injury of vascular endothelial cells are to be investigated. Methods. Microarray analysis was employed to screen out differentially expressed circRNAs in AS. A cell model was mimicked by treating Human umbilical vein endothelial cells (HUVECs) with oxidized low-density lipoprotein (ox-LDL). circ_0026218, microRNA-338-3p (miR-338-3p) and silent information regulator 6 (SIRT6) expressions in HUVECs with ox-LDL treatment were probed by qRT-PCR. The cell proliferative capabilities were exposed by CCK-8 assay. The contents of interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor α (TNF-α) were measured by ELISA. Oxidative stress kits were utilized to detect the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA). Flow cytometry was adopted to analyze the level of apoptosis of HUVECs. Dual-luciferase reporter gene assay and RIP assay were leveraged to expose the interplay between miR-338-3p and circ_0026218 or SIRT6 3 ′ -UTR, respectively. In addition, the impacts of circ_0026216 and miR-338-3p on SIRT6 protein expressions were subjected to Western blot. Results. circ_0026218 was greatly depleted in ox-LDL-stimulated HUVECs. circ_0026218 overexpression promoted viability of HUVECs in vitro and inhibited inflammatory response, oxidative stress, and apoptosis. circ_0026218 could adsorb miR-338-3p and positively modulated SIRT6 expressions via sponging miR-338-3p. Upregulation of this miRNA reversed the influence of circ_0026218 overexpression on ox-LDL-caused injury and apoptosis of HUVECs. Conclusion. Collectively, circ_0026218 upregulates SIRT6 expression through decoying miR-338-3p, thereby inhibiting ox-LDL-initiated injury of HUVECs. circ_0026218 is involved in the pathogenesis of AS.

Circular RNA: A new expectation for cardiovascular diseases

“…circ_0008896 is involved in oxidative LDL‐induced aortic endothelial cell injury as well by targeting the miR‐188‐3p/NOD2 axis 47 . Likewise, circ_0029589, 48 circ_0026218 49 and circ_0004104 50 take effect in oxidative LDL‐induced endothelial cell injury through miRNA sponge.…”

The role of mammalian Sirtuin 6 in cardiovascular diseases and diabetes mellitus

“…Additionally, accumulation of oxidized low-density lipoprotein (ox-LDL) precipitates atherosclerosis which features oxidative stress. A most recent paper in 2023 reported that Circ_0026218 overexpression dampens oxidative stress damage and restores ox-LDL-induced HUVECs dysfunction via Sirt6 upregulation, implying a protective function of Sirt6 in defending oxidative stress insult ( Yang et al, 2023 ).…”

“…Several studies showed that Sirt6 actively functions as a defender against several inflammatory diseases. Latest research demonstrated that circular RNA circ_0026218 ameliorates atherosclerosis development through upregulation of Sirt6 ( Yang et al, 2023 ). Since it is generally accepted that atherosclerosis is characterized as a set of chronic inflammatory responses, Sirt6 plays a significant role in regulating inflammation.…”

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

“…Thus, circDLGAP4 became the focus of this research. In addition, circRNA/miRNA/mRNA pattern in AS has been gradually clarified 15,16 . MiRNAs can alter gene expression after transcription by targeting 3′UTRs of target mRNAs, and miRNAs themselves are associated with autophagy and endothelial cell dysfunction 17 .…”

“…In addition, circRNA/miRNA/mRNA pattern in AS has been gradually clarified. 15,16 MiRNAs can alter gene expression after transcription by targeting 3 0 UTRs of target mRNAs, and miRNAs themselves are associated with autophagy and endothelial cell dysfunction. 17 We hypothesized that circDLGAP4 may exert a role in AS in circRNA/ miRNA/mRNA pattern.…”