Abstract 13378: Atypical Mechanosensitive MicroRNA-712 Derived From Pre-ribosomal RNA Induces Endothelial Inflammation and Atherosclerosis
| Autor: | Sandeep Kumar, Dong J Son, Wakako Takabe, Chanwoo Kim, Inhwan Jang, Chih W Ni, Noah Alberts-Grill, Hanjoong Jo |
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| Rok vydání: | 2014 |
| Předmět: | |
| Zdroj: | Circulation. 130 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | 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, their role in atherosclerosis has not been directly demonstrated. We used partial carotid ligation surgery to induce d-flow in the Left carotid artery (LCA) of mouse while the contralateral right carotid artery (RCA) continued to experience stable flow (s-flow). We devised a technique to quickly extract endothelial-enriched RNA from these carotids and performed miRNA array and subsequent validations. Also, using a cone-and-plate shear device, we exposed the immortalized mouse aortic endothelial cells to either laminar or oscillatory shear stress. Use used pre-miR-712 to induce and anti-miR-712 to knockdown the expression of miR-712 in our system. 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. Using 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. 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. Targeting mechanosensitive "athero-miRs" with anti-miR-based approaches may provide a new treatment paradigm in atherosclerosis. |
| Databáze: | OpenAIRE |
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