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. Author Contribution DJS and SK contributed equally to the manuscript. DJS, SK, WT, CN, JWS and KWF designed the experiments. DJS, SK, WT, CN, CW, JWS, SK, IHJ and NAG performed the experiments. DJS, WT, SK, CN, CWK, SOK, WKK, JWS, and NAG analyzed the data. AHB and KWF provided key reagents. SK, DJS, and HJ wrote the manuscript. HJ supervised the overall research, secured funding, designed experiments and interpreted results and wrote the manuscript. Accession codesThe microarray data have been deposited in NCBI's Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE52243.Conflict of Interest None. 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 flowdependent manner. Targeting these mechanosensitive "athero-miRs" may provide a new treatment paradigm in atherosclerosis. HHS Public Access

Affinity-Driven Design of Cargo-Switching Nanoparticles to Leverage a Cholesterol-Rich Microenvironment for Atherosclerosis Therapy

“…To observe the accumulation of CSNP in plaque and other organs, we used a partial carotid ligation model that forms robust atherosclerosis in the left carotid artery (LCA) of ApoE −/− mice within 2 weeks. 41,42 CSNP were injected intravenously on days 8 and 11 after left carotid ligation (Figure 3B). The mice were sacrificed 3 days after the last injection of CSNP to analyze plaque targeting and biodistribution of CSNP.…”