Abstract 17664: Role of miR-92a for Endothelial Cell Function and Reendothelialization Following Vascular Injury
Background: MicroRNAs (miR) are small noncoding RNAs that regulate gene expression by binding to the cellular transcript leading to translational repression or degradation of the target mRNA. So far, the impact of specific microRNAs on atherosclerosis and restensosis following vascular injury is widely unknown.
Methods/Results: Aortic arches of ApoE/LDLr−/− mice were isolated and differential expression of miRs was assessed by microarrays analysis after 2 weeks (control), 6 and 12 months. Neointima formation was induced in C57BL6/N by dilation of the femoral artery and miR was isolated and subjected to microarrays analysis at 10 and 21 days after injury. Here as well as during atherosclerosis development, the majority of all known miRs was dysregulated. Noticeably, miR-92a was significantly upregulated during the development of atherosclerosis (12 months; 1.9-fold) as well as restenosis (10d: 2.5-fold; 21d: 2.5–1.9-fold), which was confirmed by subsequent qPCR analysis. Further expression analysis revealed that miR-92a, one of the most strongly regulated miRs, is highly expressed in human coronary artery endothelial cells (ECs) but to a much lower extent in smooth muscle cells. miR-92a inhibition in vitro significantly increased the proliferation of ECs as assessed by BrdU incorporation. Moreover, inhibition of mir-92a expression in vivo by systemic application of LNA-modified, stable antisense molecules following wire-induced injury of the femoral artery resulted in a significant acceleration of reendothelialization of the denuded vessel area at 10 days following injury (69±7 vs. 42±9% n=6; p<0.001). In ongoing experiments, we are evaluating the effect of an accelerated reendothelialization on neointima formation.
Conclusions: These data provide evidence, that the expression of miRs is strongly regulated during the development of atherosclerosis and restenosis. Specifically, miR-92a is upregulated in dysfunctional and regenerating endothelial cells and its inhibition increases the healing- and reendothelialization capacity of EC at vascular lesion sites, thus representing a putative novel target to enhance the functional recovery following acute or chronic vascular injury.
- © 2010 by American Heart Association, Inc.