Abstract 640: Role of MicroRNA-146a in Vascular Inflammation and Atherosclerosis

Abstract

Prolonged activation of inflammatory pathways in the endothelium leads to vascular diseases, including sepsis and atherosclerosis. During this process, activated endothelial cells recruit circulating leukocytes by expressing adhesion molecules and chemoattractants, such as vascular cellular adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1), respectively. Down-regulation of the anti-adhesion molecule, nitric oxide, which is synthesized by endothelial nitric oxide synthase (eNOS), is also a critical step during endothelial activation. Here we demonstrate that microRNA-146a and microRNA-146b are upregulated in endothelial cells upon exposure to the pro-inflammatory cytokine, interleukin-1-beta (IL-1β). Over expression of miR-146 in endothelial cells dampens the inflammatory response induced by IL-1β and conversely inhibition of endogenous miR-146 in vitro or deletion of miR-146a in vivo exacerbates the inflammatory response to IL-1β. We found that miR-146 represses VCAM-1 and MCP-1 expression by impinging on the canonical NF-kB pathway by targeting the upstream adaptor proteins TRAF6 and IRAK1. In addition, we identified the RNA-binding protein, HuR, as a novel miR-146 target. Knock-down of HuR results in an increase in eNOS expression and a corresponding decrease in leukocyte adhesion, which parallels with the miR-146 over expression phenotype. Considering the involvement of miR-146a in regulating vascular inflammation, miR-146a-/-; Ldlr-/- mice (DKO) were generated to assess atherogenesis. After 12 weeks on high cholesterol diet, the DKO mice developed more lipid-rich plaques in the lesser curvature of the aortic arch compared to Ldlr-/- mice. This suggests that miR-146a may have atheroprotective properties in addition to its anti-inflammatory role in acute inflammation.