Research Paper Volume 13, Issue 8 pp 11610—11628
circACTA2 mediates Ang II-induced VSMC senescence by modulation of the interaction of ILF3 with CDK4 mRNA
- 1 Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China
- 2 Department of Urology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
- 3 Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai 264003, China
Received: September 12, 2020 Accepted: March 13, 2021 Published: April 22, 2021https://doi.org/10.18632/aging.202855
How to Cite
Copyright: © 2021 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Chronic angiotensin II (Ang II) stimulation induces vascular smooth muscle cell (VSMC) senescence, and circRNAs and members of the ILF3 family are implicated in cellular senescence, but the mechanism underlying regulation of circRNAs and ILF3 by Ang II in VSMCs remains poorly understood. Here, a model of Ang II-induced VSMC senescence and the renal artery of hypertensive patients were used to investigate the roles and mechanisms of circACTA2 and ILF3 in VSMC senescence. We show that circACTA2 expression was elevated in Ang II-stimulated VSMCs and in the vascular walls of hypertensive patients. circACTA2 knockdown largely abrogated Ang II-induced VSMC senescence as shown by decreased p21 expression and increased CDK4 expression as well as by decreased SA β-gal-positive cells. Oligo pull-down and RIP assays revealed that both circACTA2 and CDK4 mRNA could bind with ILF3, and Ang II facilitated circACTA2 association with ILF3 and attenuated ILF3 interaction with CDK4 mRNA. Mechanistically, increased circACTA2 by Ang II reduced ILF3 association with CDK4 mRNA by competing with CDK4 mRNA to bind to ILF3, which decreases CDK4 mRNA stability and protein expression, thus leading to Ang II-induced VSMC senescence. Targeting the circACTA2-ILF3-CDK4 axis may provide a novel therapeutic strategy for VSMC senescence-associated cardiovascular diseases.