Committee:

Michael Davis, Ph.D. (Georgia Institute of Technology & Emory University)

Charles Searles Jr., M.D. (Emory School of Medicine)                                                  

Loren Williams, Ph.D. (Georgia Institute of Technology)                                                   

Younan Xia, Ph.D. (Georgia Institute of Technology)                                                  

miR-744 Modulation by Disturbed Flow and its Role in Endothelial Inflammation and Atherosclerosis

 Atherosclerosis is the leading cause of death in developed nations as it is the underlying cause of many cardiovascular diseases (CVD) such as myocardial infarction, ischemic stroke, and peripheral arterial disease. Atherosclerotic plaques preferentially develop in areas with curved or branched geometries due to the effects of low magnitude, oscillating, disturbed blood flow (d-flow) on the endothelium. The mechanisms by which d-flow induces pro-atherogenic responses predominantly involves changes in the endothelial gene expression, in part due to differential microRNA (miRNA) expression. Here, we report the identification of a novel, flow-sensitive miR-744 in endothelial cells that stimulates endothelial inflammation in vitro. Furthermore, we found LIMS2 is a novel, mechanosensitive, conserved target of miR-744. Finally, inhibition of the specific interaction of miR-744 and LIMS2 by target site blockers significantly reduced the development of plaque in a d-flow-induced murine model of atherosclerosis. The work presented here has resulted in the discovery of a novel, atherogenic miRNA, a novel, atheroprotective gene, and underscores the importance of the specificity of the miRNA-gene interaction. This work also provides a foundation for future studies to develop more targeted therapeutic strategies for CVD.