CircANKRD12 Is Induced in Endothelial Cell Response to Oxidative Stress

Abstract

Redox imbalance of the endothelial cells (ECs) plays a causative role in a variety of cardiovascular diseases. In order to better understand the molecular mechanisms of the endothelial response to oxidative stress, the involvement of circular RNAs (circRNAs) was investigated. CircRNAs are RNA species generated by a "back-splicing" event, which is the covalent linking of the 3'- and 5'-ends of exons. Bioinformatics analysis of the transcriptomic landscape of human ECs exposed to H2O2 allowed us to identify a subset of highly expressed circRNAs compared to their linear RNA counterparts, suggesting a potential biological relevance. Specifically, circular Ankyrin Repeat Domain 12 (circANKRD12), derived from the junction of exon 2 and exon 8 of the ANKRD12 gene (hsa_circ_0000826), was significantly induced in H2O2-treated ECs. Conversely, the linear RNA isoform of ANKRD12 was not modulated. An increased circular-to-linear ratio of ANKRD12 was also observed in cultured ECs exposed to hypoxia and in skeletal muscle biopsies of patients affected by critical limb ischemia (CLI), two conditions associated with redox imbalance and oxidative stress. The functional relevance of circANKRD12 was shown by the inhibition of EC formation of capillary-like structures upon silencing of the circular but not of the linear isoform of ANKRD12. Bioinformatics analysis of the circANKRD12–miRNA–mRNA regulatory network in H2O2-treated ECs identified the enrichment of the p53 and Foxo signaling pathways, both crucial in the cellular response to redox imbalance. In keeping with the antiproliferative action of the p53 pathway, circANKRD12 silencing inhibited EC proliferation. In conclusion, this study indicates circANKRD12 as an important player in ECs exposed to oxidative stress.

Modulation of atherosclerosis‐related signaling pathways by Chinese herbal extracts: Recent evidence and perspectives

“…IFN‐γ promptly phosphorylates STAT1 and STAT6, thereby inhibiting TRAIL‐mediated endothelial cell apoptosis (Ge et al, 2019). Additionally, miRNAs play pivotal roles in vascular endothelial injury; for instance, miRNA‐126 can enhance endothelial integrity and vascular regeneration, while miRNA‐210 regulates the transcription and translation processes of NOS genes via the JAK/STAT signaling pathway, participating in critical processes such as NO production and the proliferation and apoptosis of vascular endothelial cells (Noone et al, 2023; Tanaka et al, 2005; Voellenkle et al, 2022). Thus, both the JAK/STAT pathway and miRNA are critical in endothelial cell injury, potentially impacting the functionality and disease progression of vascular endothelial cells.…”

Cardiovascular complications of diabetes: role of non-coding RNAs in the crosstalk between immune and cardiovascular systems

“…CircRNAs are mostly known for their ability to ‘sponge’ miRNAs but may have other important functions such as interaction with RNA-binding proteins, directing their interaction with downstream target proteins or mRNAs. Moreover, a small subset of circRNAs is translated [ 43 – 46 ]. lncRNAs are involved in all forms of human physiology and pathology [ 47 ], but due to lower conservation, their study using animal models is methodologically more challenging.…”