Abstract 14556: Role of miR-146a for Smooth Muscle Cell- and Endothelial Cell Function During Neointima Formation
Background: MicroRNAs (miRNAs) are a new class of small noncoding RNA molecules, comprising key regulators for major cellular events including proliferation, differentiation and apoptosis. It is now apparent that abnormal miRNA expression is a common feature of human diseases. The miRNA expression during the development of restenosis still remains elusive. Targeting miRNAs that influence cellular functions may offer an interesting approach for the prevention or treatment of vascular proliferative diseases.
Methods/Results: Using microarray based expression analysis we screened for regulated miRNAs during the development of restenosis. Neointima formation was induced in C57BL6/N by dilation of the femoral artery and miRNA was isolated 10 and 21 days after injury. The majority of all known miRNAs was found to be aberrantly regulated. Noticeably, miR-146a was significantly upregulated during restenosis. Further expression analysis in isolated primary vascular cell types revealed that miR-146a was highly expressed in endothelial cells (ECs) and to a lower extent in vascular smooth muscle cells (VSMCs). In vitro, the upregulation of miR-146a could be attributed to inflammatory factors rather than mitogenic or apoptotic stimuli. To further assess the functional role of miR-146a, VSMCs and ECs were transfected with miR-146a inhibitors resulting in a significantly increased proliferation, total cell count and migration of ECs. Furthermore, apoptosis of ECs was reduced following miR-146a inhibition. In VSMCs, the knock down of miR-146a led to an opposite effect, namely a reduction of proliferation, total cell count and migration. In complementing in vivo experiments, the inhibition of miR-146a upregulation/expression in injured murine femoral arteries significantly accelerated reendothelialization and inhibited the proliferation of neointimal VSMCs, resulting in a significantly reduced neointima formation.
Conclusion: These findings reveal a pivotal role of miR-146a for vascular cell function, especially under conditions of pathological vascular remodeling processes. Thus, modulating miR-146a expression may represent a novel approach for the prevention and treatment of vascular proliferative diseases.
- © 2011 by American Heart Association, Inc.