Abstract 20060: miR-155 a Possible Mediator of Acute Oscillatory Shear Stress (OSS)-Induced Oxidative Stress, Inflammation & Vascular Dysfunction
Introduction: Shear stress forces play an integral role in dictating the endothelial cell (EC) response to changes in blood flow, induction of pro-inflammatory and oxidative stress and hence development of atherosclerosis. Previously, our group has identified EC microRNA-155 (miR-155) as one of the key signature dysregulated miRNAs in areas of chronic low magnitude oscillatory shear stress (OSS) in vasculature and OSS models in-vitro.
Hypothesis: we hypothesized that acute induction of OSS mediates EC oxidative stress, inflammation and dysfunction, via dysregulation of EC miR-155.
Methods: 12-week old C57B/6J mice were subjected to abdominal aortic coarctation (AAC), a unique model of acute induction of OSS, for 3 days and downstream segments of acute OSS were compared to upstream unidirectional shear stress (USS) segments of the thoracic aorta using unpaired student t-test.
Results: Acute OSS resulted in vascular inflammation evidenced by upregulation of vascular miR-155 expression and several of its validated pro-inflammatory targets including AT1Ra, phosphorylated ERK2, ETS1 and downstream 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 MMP9 and downregulation of tight junction proteins; Claudin 1 and 5 in in OSS segments compared with USS. In parallel, en-face immunohistochemical staining showed increased levels of reactive oxygen species (ROS) and nitrotyrosine (NY) formation in OSS segments compared with USS, which was accompanied by impaired EC dependent relaxation and differential contractile response to phenylephrine.
Conclusions: Together, our studies shed light on the early pro-oxidative and pro-inflammatory EC response to acute induction of OSS that was associated with impaired vascular response and loss of barrier function. Despite the early upregulation of the shear-sensitive miR-155, it could also potentially serve as a negative feedback regulator to acute OSS-induced inflammatory stress and associated EC dysfunction. Further studies are in progress to dissect the interplay between these different pathways and their causal relationships as downstream targets of EC miR-155.
Author Disclosures: I. Mohamed: None. S. Thomas: None. K. Rooney: None. R. Sutliff: None. N. Willett: None. C. Searles: None.
- © 2016 by American Heart Association, Inc.