The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis

Abstract

MicroRNAs (miRNAs) regulate cardiovascular biology and disease, but the role of flow-sensitive microRNAs in atherosclerosis is still unclear. Here we identify miRNA-712 (miR-712) as a mechanosensitive miRNA upregulated by disturbed flow (d-flow) in endothelial cells, in vitro and in vivo. We also show that miR-712 is derived from an unexpected source, pre-ribosomal RNA, in an exoribonuclease-dependent but DiGeorge Syndrome Critical Region-8 (DGCR8)-independent manner, suggesting that it is an atypical miRNA. Mechanistically, d-flow-induced miR-712 downregulates tissue inhibitor of metalloproteinase-3 (TIMP3) expression, which in turn activates the downstream matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) and stimulate pro-atherogenic responses, endothelial inflammation and permeability. Furthermore, silencing miR-712 by anti-miR-712 rescues TIMP3 expression and prevents atherosclerosis in murine models of atherosclerosis. Finally, we report that human miR-205 shares the same “seed sequence” as murine-specific miR-712, and also targets TIMP3 in a flow-dependent manner. Targeting these mechanosensitive “athero-miRs” may provide a new treatment paradigm in atherosclerosis.

MiR‐152 reduces human umbilical vein endothelial cell proliferation and migration by targeting ADAM17

“…Members of the ADAMs family (ADAM 8,9,10,12,15,17,19 and 28) are expressed widely in epithelial cells, smooth muscle cells and leukocytes [3,4]. As a well-known ectodomain sheddase, ADAM17 plays an important role in vascular physiological and pathological processes through regulating membrane-anchored protein maturation [5].…”

Targeted Delivery of Shear Stress-Inducible microRNAs by Nanoparticles to Prevent Vulnerable Atherosclerotic Lesions

“…Notably, several microRNAs have been identified as being regulated by shear stress, including miR-92a, miR-21, miR-663, miR-19, miR-126, and the miR-143/145 cluster. [34][35][36][37][38][39][40] However, the effect of shear stress on microRNA expression and function in the vasculature during the development of atherosclerotic plaques is poorly understood.…”

RNA interference in early branching metazoans

“…The only miRNAs confirmed to have been derived from ribosomal transcripts are mouse miR-712 and human miR-663, both of which are located on ITS regions of their respective rRNA polycistrons (Son et al 2013, Waaijer et al 2014. This also makes them the only known miRNAs to be the products of RNA polymerase I transcription.…”

“…These populations of small RNAs often show non-random distributions when mapped across consensus rRNA sequences and possess read-length distributions that are not indicative of degradation products. Only two confirmed miRNAs are known to come from a ribosomal transcript -the mouse specific miR-712 which is located in the internal transcribed spacer 2 (ITS2) between the 5.8S and the 28S rRNA subunits (Son et al 2013) and miR-663 in humans which lies in ITS1 (Waaijer et al 2014).…”

“…ITS2 derived miR-712 follows an atypical biogenesis pathway that is independent of both DGCR8 (Drosha) and Dicer (Son et al 2013). The only enzyme known to impact miR-712 expression is XRN1, an exonuclease capable of removing ITS2 from the 25.5S…”