Send to

Choose Destination
Circ Res. 2018 Nov 30. doi: 10.1161/CIRCRESAHA.118.314240. [Epub ahead of print]

Circ_Lrp6, a Circular RNA Enriched in Vascular Smooth Muscle Cells, Acts as a Sponge Regulating miRNA-145 Function.

Author information

Cardiovascular Medicine, Humanitas Clinical and Research Center.
Medicine, Multimedica Research Hospital.
Advanced Optical Microscopy, Humanitas Clinical and Research Center.
Molecular and Translational Medicine, University of Brescia.



microRNAs (miRNAs) modulate gene expression by repressing translation of targeted genes. Previous work has established a role for miRNAs in regulating vascular smooth muscle cell (VSMC) activity. Whether circular RNAs (circRNA) are involved in the modulation of miRNA activity in VSMCs is unknown.


We aimed to identify circRNAs interacting with miRNAs enriched in VSMCs and modulating the cells' activity.


RNA sequencing and bioinformatics identified several circRNAs enriched in VSMCs; however, only one, possessing multiple putative binding sites for miR-145, was highly conserved between mouse and man. This circRNA gemmed from alternative splicing of lipoprotein receptor 6 (Lrp6), a gene highly expressed in vessels and implicated in vascular pathologies, and was thus named circ_Lrp6. Its role as a miR-145 sponge was confirmed by determining reciprocal interaction through RNA immunoprecipitation, stimulated emission depletion microscopy, and competitive luciferase assays; functional inhibition of miR-145 was assessed by measuring expression of the target genes ITGβ8, FASCIN, KLF4, Yes1, and Lox. The interaction was preferentially localized to P-bodies, sites of mRNA degradation. Using loss- and gain-of-function approaches, we found that circ_Lrp6 hindered miR-145-mediated regulation of VSMC migration, proliferation, and differentiation. Differential expression of miR-145 and circ_Lrp6 in murine and human vascular diseases suggests that the ratio of circ_Lrp6 bound to miR145 vs. unbound could play a role in vascular pathogenesis. Viral delivery of circ_Lrp6 shRNA prevented intimal hyperplasia in mouse carotids.


circ_Lrp6 is an intracellular modulator and a natural sponge for miR-145, counterbalancing the functions of the miRNA in VSMCs.


circular RNA

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center