Figure 8: Summary and working hypothesis.

miR-712 induces inflammation and atherosclerosis by targeting TIMP3. D-flow stimulates miR-712 expression in endothelium by an XRN1-dependent mechanism. Increased miR-712 stimulates endothelial inflammation, permeability and extracellular matrix (ECM) fragmentation by downregulating TIMP3, which is a critical inhibitor of matrix metalloproteinases (MMPs and ADAMs). Decreased TIMP3 expression by miR-712 induces inflammation and atherosclerosis by activating a multitude of metalloproteinases: (1) ADAM17/TACE that releases soluble-TNFα that may induce local and systemic inflammation; (2) ADAMs that shed junctional VE-cadherin, increasing permeability that facilitates LDL and leukocyte infiltration; (3) ADAMTS leading to versican fragmentation; and (4) MMPs leading to ECM degradation leading to vessel wall remodeling. In addition, miR-712 expression is also increased in whole blood and vascular smooth muscle cells (VSMCs) suggesting either transfer of miR-712 from endothelium to these compartments or increase in its local production in these compartments. Increased miR-712 in VSMCs induces their migration while circulating miR-712 may affect blood leukocytes further contributing to atherogenesis.