Abstract 258: Mir-155 Mitigates Acute Oscillatory Shear Stress (OSS)-Induced Vascular Inflammation and Barrier Dysfunction Through Down Regulation of the AT1R-ETS1 Pathway

Abstract

Introduction: Shear stress forces play an integral role in dictating the vascular wall response to changes in blood flow, induction of pro-inflammatory response and hence development of atherosclerosis. Previously, our group and others have identified an inverse relationship between microRNA-155 (miR-155) and AT1R expression and/or activity in atheroprone areas of chronic low magnitude oscillatory shear stress (OSS) in vasculature and in-vitro. Hypothesis: we hypothesized that acute induction of OSS mediates vascular inflammation and dysfunction, via activation of the AT1R-ETS1 pathway and dysregulation of miR-155. Methods: 12-week old C57B/6J mice were subjected to abdominal aortic coarctation (AAC), a unique model of acute induction of acute OSS, for 3 days. Downstream segments of acute OSS were compared to upstream unidirectional shear stress (USS) segments of the thoracic aorta using RT-PCR, western blot analysis and unpaired student t-test. Results: Acute OSS resulted in vascular inflammation evidenced by upregulation of the AT1R-ETS1 pathway and several of its downstream targets including phosphorylated ERK2, MCP-1 and VCAM-1 in OSS segments compared with USS. This was associated with loss of EC barrier function as evaluated by extravasation of Evans-blue dye assay along with increased expression of MMP3 and MMP9 in in OSS segments compared with USS. However, vascular miR-155 expression was also higher in OSS segments compared with USS (n=6-12, P<0.05). Nevertheless, tail vein injections of miR-155 overexpressing lentivirus particles after AAC resulted in further upregulation of miR-155 expression and inverse downregulation of the AT1R-ETS1 pro-inflammatory pathway and MMPs 3 and 9 expression in OSS segments compared with USS versus scramble control (n=5-6, P<0.05). Conclusions: Despite the early upregulation of the shear-sensitive miR-155, our data suggest that it could serve as a negative feedback regulator to acute OSS-induced upregulation of the pro-inflammatory AT1R-ETS1 pathway. Further studies are in progress to evaluate the effect of exogenous miR-155 on OSS-induced oxidative stress and vascular dysfunction, which can serve as the basis for developing novel miRNA-based therapeutic modalities.