Cited 23 times since 2020 (6.2 per year) source: EuropePMC Molecular therapy. Nucleic acids, Volume 21, 21 3 2020, Pages 932-953 Adenosine-to-Inosine Editing of Vasoactive MicroRNAs Alters Their Targetome and Function in Ischemia. van der Kwast RVCT, Parma L, van der Bent ML, van Ingen E, Baganha F, Peters HAB, Goossens EAC, Simons KH, Palmen M, de Vries MR, Quax PHA, Nossent AY

Adenosine-to-inosine (A-to-I) editing in the seed sequence of microRNAs can shift the microRNAs' targetomes and thus their function. Using public RNA-sequencing data, we identified 35 vasoactive microRNAs that are A-to-I edited. We quantified A-to-I editing of the primary (pri-)microRNAs in vascular fibroblasts and endothelial cells. Nine pri-microRNAs were indeed edited, and editing consistently increased under ischemia. We determined mature microRNA editing for the highest expressed microRNAs, i.e., miR-376a-3p, miR-376c-3p, miR-381-3p, and miR-411-5p. All four mature microRNAs were edited in their seed sequence. We show that both ADAR1 and ADAR2 (adenosine deaminase acting on RNA 1 and RNA 2) can edit pri-microRNAs in a microRNA-specific manner. MicroRNA editing also increased under ischemia in vivo in a murine hindlimb ischemia model and ex vivo in human veins. For each edited microRNA, we confirmed a shift in targetome. Expression of the edited microRNA targetomes, not the wild-type targetomes, was downregulated under ischemia in vivo. Furthermore, microRNA editing enhanced angiogenesis in vitro and ex vivo. In conclusion, we show that microRNA A-to-I editing is a widespread phenomenon, induced by ischemia. Each editing event results in a novel microRNA with a unique targetome, leading to increased angiogenesis.

Mol Ther Nucleic Acids. 2020 7;21:932-953