MECHANOSENSITIVE MICRORNAS IN ENDOTHELIAL INFLAMMATION AND ATHEROSCLEROSIS: PREVENTION OF ATHEROSCLEROSIS BY ANTI-MIR-712 IN MICE


Hanjoong Jo, Ph.D., Dept. of Biomedical Engineering, Emory University, Atlanta, GA, USA

Atherosclerosis is the major underlying cause of myocardial infarction and stroke and preferentially occurs in arterial regions exposed to disturbed flow (d-flow) by mechanisms involving broad changes in gene expression. We have shown that D-flow rapidly induces atherosclerosis in vivo using a mouse partial carotid ligation model. In addition, we developed a novel intimal RNA preparation method using this animal model and identified numerous mechanosensitive endothelial genes that change in response to d-flow. Some of these mechanosensitive genes are regulated by microRNAs (miRNAs). While miRNAs are known to regulate various aspects of cardiovascular biology and disease, their role in atherosclerosis is unclear. Recently, we identified novel mechanosensitive miRNAs using the same mouse model and endothelial miRNA array. Here we identified that atypically derived mechanosensitive microRNA, miR-712, as the most shear-sensitive miRNA upregulated by d-flow both in vivo and in vitro. Mechanistically, d-flow-induced miR-712 directly downregulates tissue inhibitor of metalloproteinase 3 (TIMP3) expression that in turn activates the downstream metalloproteinases and stimulate pro-atherogenic responses and endothelial inflammation. Further, subcutaneously injected anti-miR-712 silences miR-712 and rescues TIMP3 expression, and prevents atherosclerosis in two independent murine models of atherosclerosis. Localized overexpression of TIMP3 also inhibits lesion development supporting the critical role of TIMP3 in atherosclerosis. Our results suggest that targeting mechanosensitive "athero-miRs" with anti-miR-based approaches may provide a new treatment paradigm in atherosclerosis.