Circ_0000006 and circ_0000160 regulate hsa-let-7e-5p/UBQLN4 axis in aortic dissection progression

Abstract

Aortic aneurysms (AA) and aorta dissection (AD) are life-threatening conditions with a rising incidence and high mortality rate. Recent research has linked non-coding RNAs to the regulation of AA and AD progression. In this study, we performed circRNA sequencing, microRNA (miRNA) sequencing, and messenger RNA (mRNA) sequencing on plasma samples from AA and AD patients to identify the key circRNA-miRNA-mRNA axis involved in the transition from AA to AD. Our results showed elevated levels of circ_0000006 and circ_0000160, along with decreased levels of hsa-let-7e-5p in AD samples compared to AA samples. Predictive analysis suggested that circ_0000006 and circ_0000160 potentially target hsa-let-7e-5p, which in turn may bind to the mRNA of Ubiquilin 4 (UBQLN4). In an AD cell model using vascular smooth muscle cells (VSMCs), silencing circ_0000006 and circ_0000160 attenuated the effects of platelet-derived growth factor (PDGF)-induced phenotypic changes, proliferation, and migration. This effect was partially reversed by inhibiting hsa-let-7e-5p. Furthermore, we found that overexpression of UBQLN4 counteracted the effects of hsa-let-7e-5p, suggesting UBQLN4 as a downstream mediator of hsa-let-7e-5p. In an animal model of AD, knockdown of circ_0000006 and circ_0000160 also showed protective effects against aortic septation. Overall, our findings indicate that the upregulation of circ_0000006 and circ_0000160 contributes to the progression from AA to AD by influencing abnormal phenotypic changes, migration, and proliferation of VSMCs. The Hsa-let-7e-5p/UBQLN4 axis may play a critical role in AD development. Targeting circ_0000006 and circ_0000160 could be a potential therapeutic strategy for preventing the progression of AD.