Abstract 15696: Inhibition of Mechanosensitive MicroRNA, mir-712 Decreases Endothelial Dysfunction and Atherosclerosis
Atherosclerosis is the underlying cause of cardiovascular events, such as heart attack and stroke, and preferentially occurs in arterial regions exposed to disturbed flow (d-flow) by mechanisms involving broad changes in gene expression. While microRNAs (miRNAs) are known to regulate various aspects of cardiovascular biology and disease, their role in atherosclerosis has not been directly demonstrated. Here, we identified mechanosensitive miRNAs using a mouse partial carotid ligation model and endothelial miRNA array. Of those mechanosensitive miRNAs identified, miR-712 was the most shear-sensitive miRNA upregulated by d-flow both in vivo and in vitro. We found that miR-712 is derived from the internal transcribed spacer 2 (ITS2) region of pre-ribosomal RNA (RN45S gene) in a XRN1 exonuclease-dependent, but DGCR8-independent manner, suggesting that it is an atypical miRNA derived from an unexpected source. Studies including gain-of-function (pre-miR-712) and loss-of-function (anti-miR-712) approaches and target-binding assays showed that miR-712 directly downregulated the tissue inhibitor of metalloproteinase 3 (TIMP3) expression. This in turn activated downstream metalloproteinases (MMPs and ADAM family) and stimulated pro-atherogenic responses, endothelial tubule formation and sprouting, in a flow-dependent manner. Further, treatment with anti-miR-712 prevented atherosclerosis in two different models of murine atherosclerosis using ApoE-/- mice: a chronic conventional western-diet or an acute carotid partial ligation model on a high-fat diet. Our results suggest that targeting mechanosensitive "athero-miRs" with anti-miR-based approaches may provide a new treatment paradigm in atherosclerosis.
- © 2013 by American Heart Association, Inc.