Circular RNA circGNAQ acts as the sponge of miR-146a-5p to delay endothelial cell senescence and atherosclerosis progression
Endothelial cell senescence is one of the most important causes of vascular dysfunction and atherosclerosis. Circular RNAs (circRNAs) are endogenous RNA molecules with covalently closed-loop structures, which have been reported to be abnormally expressed in many human diseases. However, the potential role of circRNAs in endothelial cell senescence remains unknown. Here, we compared the expression patterns of circRNAs in young and senescent human endothelial cells using RNA sequencing. Among the differentially expressed endothelial cell senescence-associated circRNAs, we identified circGNAQ, generated by circularization of exons 4 and 5 of the GNAQ gene, as a circRNA showing markedly reduced levels in senescent endothelial cells. CircGNAQ silencing in young endothelial cells triggered senescence, as determined by a rise in senescence-associated ß-galactosidase activity, reduced cell proliferation, and suppressed angiogenesis; circGNAQ overexpression showed the opposite effects. Mechanistic studies revealed that circGNAQ acted as an endogenous miR-146a-5p sponge to sequester and inhibit miR-146a-5p activity, leading to increased PLK2 expression. In vivo studies showed that circGNAQ overexpression delayed endothelial cell senescence and atherosclerosis progression in ApoE-/- mice. These results revealed an important role for circGNAQ in cellular senescence and provide novel insight into the role of circRNAs in atherosclerosis progression. Overall design: circRNA sequencing on ribosomal RNA-depleted total RNA from young and senescent endothelial cells (HUVECs and HCAECs)