Circular RNA profiling reveals an abundant circPTK2 that contributes everolimus-induced endothelial cell dysfunction...

mTOR inhibitors released from drug-eluting stents (DESs) play a critical role in the pathogenesis of in-stent neoatherosclerosis (ISNA), contributing to the development of late in-stent restenosis (ISR). Circular RNAs (circRNAs) are emerging as key regulators in various pathophysiological processes, but their involvement in ISNA remains unclear.

The expression pattern of circRNAs in human umbilical vein endothelial cells (HUVECs) treated with everolimus (EVL) was analysed using RNA sequencing. The expression levels of circRNAs, miR-1-5p, and the downstream targets ACVR2B/StarD13 were measured by quantitative real-time PCR. The effects of circPTK2 on cell proliferation, migration, apoptosis, and permeability in EVL-treated endothelial cells were assessed using cell counting kit-8, scratch, Annexin-V FITC and PI double-staining, and transwell assays. Bioinformatics analysis and dual luciferase assay were used to identify the interaction between circPTK2 and miR-1-5p. The association between circPTK2, miR-1-5p, and ACVR2B/StarD13 was further evaluated by functional rescue experiments.

CircPTK2 was significantly upregulated in EVL-treated HUVECs. Knockdown of circPTK2 reversed the EVL-induced suppression of cell viability and migration, reduced apoptosis, and alleviated endothelial barrier leakage. Conversely, circPTK2 overexpression produced the opposite effects. Mechanistically, circPTK2 acted as a sponge for miR-1-5p, leading to increased expression of its target genes ACVR2B and StarD13. Silencing ACVR2B or StarD13 partially attenuated the exacerbating effects of miR-1-5p inhibition on EVL-induced endothelial dysfunction. Moreover, inflammatory conditions affected the expressions of circPTK2, miR-1-5p, and ACVR2B/StarD13.

CircPTK2 regulates EVL-induced endothelial dysfunction via the miR-1-5p/ACVR2B/StarD13 axis, providing novel insights for the treatment of late ISR after DES implantation.