Abstract 19313: MicroRNA-146a Augments Vascular Smooth Muscle Cell Proliferation and Neointima Formation
Background: Micro RNAs (miRNAs) are implicated to regulate mRNA levels in a post transcriptional manner, comprising key regulators for cellular function including proliferation, differentiation and apoptosis. Up to now, the role of miRNAs for vascular smooth muscle cell function remains elusive.
Hypothesis: The aim of this study was to evaluate the regulation and impact of miR 146a for smooth muscle cell function during the development of neointimal lesions in vitro and in vivo.
Methods/Results: Neointima formation was induced in C57BL6/N by dilation of the femoral artery and miRNA was isolated 10 and 21 days after injury. Using microarray analysis, miR-146a was found to be one of the most strongly up-regulated miRNAs during neointima formation. Further expression analysis in isolated primary vascular cell types revealed that miR-146a, besides in monocytes/macrophages and in endothelial cells, was highly expressed in vascular smooth muscle cells. In vitro, the upregulation of miR-146a could be attributed to the inflammatory stimulus Il-1β. IRAK1, a key adapter molecule in TLR- and IL-1 receptor signaling cascades, was identified as a molecular target of 146a. Indeed, IRAK1 was found down-regulated on the mRNA and protein level after transfection of SMC with miR-146a mimics and could be confirmed as direct target using luciferase reporter assays. To further assess the functional role of miR-146a, smooth muscle cells were transfected with miR-146a inhibitors. miR-146a inhibition resulted in a significantly decreased total cell count and migration of smooth muscle cells. In complementing in vivo experiments, the inhibition of miR-146a in injured murine femoral arteries significantly reduced the proliferation of neointimal smooth muscle cells as assessed by Ki67 staining. Moreover, morphometric analysis revealed a significantly attenuated neointima formation following 146a inhibition.
Conclusion: These findings reveal a pivotal role of miR-146a for function in vascular smooth muscle cells, 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.
Author Disclosures: R. Teske: None. J. Daniel: None. J. Dutzmann: None. J. Bauersachs: None. D. Sedding: None.
- © 2014 by American Heart Association, Inc.