Biology

Dr. Sandeep Kumar
Emory University, USA

Using -omics based approaches, we identified 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. Using gain-of-function and loss-of-function approaches, we identified that 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. Importantly, silencing miR-712 by anti-miR-712 rescues TIMP3 expression and prevents atherosclerosis in murine and porcine models of atherosclerosis.

Targeting these mechanosensitive 'athero-miRs' may provide a new treatment paradigm in treatment of atherosclerosis and other cardiovascular disease.