Abstract P3036: Circular RNA Decoys Targeting MiR-146a As A Promising Therapeutic Strategy To Improve Vascular Regeneration

Abstract

Heart failure and cardiac remodeling following myocardial infarction (MI) depend on capillary density and neovascularization. MicroRNAs (miRNAs), which are small non-coding RNAs that modulate gene expression, play a major role in the pathogenesis of these conditions. Inhibition of these pathways through miRNA sponges, such as antagomiRs or circular decoys (circRNAs), might represent a therapeutic approach for MI. Here, we evaluate the role of miR-146a and present a promising treatment strategy using synthetically designed circular decoys. miRNA-146a expression was analyzed in human vascular cells and mice tissue following either myocardial infarction or hind limb ischemia. CircRNAs were synthetically designed and evaluated. Methods to characterize the effect of inhibition of miR-146a included the quantification of the target gene and protein expression and analysis of cellular functions.miR-146a was significantly upregulated in vitro in senescent cells ( P <0.05) and in vivo in the ischemic myocardium following ligation of the LAD ( P <0.001) in C57BL/6 mice. A circular RNA decoy targeting miR-146a was successfully designed and transfected into vascular cells in vitro . The following analysis showed a significant target upregulation for NOX4, KLF4, and TRAF6 ( P <0.001) after circRNA transfection, also compared to antagomiR transfected cells. Functional analysis revealed improved migration and proliferation capacity in vascular endothelial cells ( P <0.05). First results indicate that inhibition of the upregulation of endothelial miR-146a in mice results in significantly enhanced angiogenesis and revascularization ( P <0.05) accompanied by a significantly reduced myocardial infarct size ( P <0.01) and preserved cardiac function post-MI ( P <0.01). In summary, we could identify miR-146a as a critical regulator of angiogenesis and vascular regeneration, and present a first strategy for angiogenic therapy of ischemic diseases. However, in vitro analysis showed a higher efficiency of circRNAs in the context of inhibiting miR-146a functions in vascular cells. CircRNAs are more stable and more efficient when transfected, compared to antagomiRs, and might be a better alternative and a realistic approach for future clinical studies.