Atheroprotective miRNA Signaling Pathways

Atheroprotective miRNA-Signaling Figure 5

MicroRNA (miRNA) are continually being identified as essential regulators of gene expression in a wide variety of different cellular contexts. A study published in March of 2012 in Nature Cell Biology1 identified an atheroprotective miRNA signaling pathway in which the miR-143/145 gene cluster is upregulated in endothelial cells and transferred to underlying smooth muscle cells (SMCs) via extracellular vesicles. Increased sheer stress of endothelial cells in vitro induced miR-143/145 gene expression via the transcription factor KLF2. In turn, miR-143/145 were packaged into extracellular vesicles that signaled to nearby SMCs. miRs 143 and 145 targeted and repressed several genes in SMCs, including ELK1 and KLF4, in an atheroprotective manner. Taking these studies a step farther, ApoE-/- mice were used to study the in vivo development of atherosclerotic lesions in the presence of injected vesicles derived from mock- or KLF2-transduced endothelial cells. ApoE-/- mice with KLF2-induced vesicles showed a significant reduction in atherosclerotic lesion size compared to vehicle control (see Figure 5 above).

These findings identified a novel and important mechanism in which extracellular miRNAs protect SMCs from de-differentiating during sheer stress conditions. To date, several more endothelial-derived miRNAs have been identified as atheroprotective, e.g. miR-1262. Future studies will be needed to identify the therapeutic potential of miRs 143, 145, and 126 for those who are prone to atherosclerotic lesions due to sheer stress conditions – such as with hypertensive individuals.

1. Hergenreider, E., Heydt, S., Treguer, K., Boettger, T., Horrevoets, A., Zeiher, A., Scheffer, M., Frangakis, A., Yin, X., Mayr, M., Braun, T., Urbich, C., Boon, R., and Dimmeler, S. Atheroprotective communication between endothelia cells and smooth muscle cells through miRNAs. Nat Cell Biol. 2012 Feb 12;14(3):249-56. doi: 10.1038/ncb244. PubMed PMID: 22327366.

2. Zhou, J., Li, YS., Nguyen, P., Wang, KC., Weiss, A., Kuo, YC., Chiu, JJ., Shyy, J., and Chien, S. Regulation of vascular smooth muscle cell turnover by endothelial cell-secreted microRNA-126. Circ Res. 2013 Jun 21;113(1):40-51. doi: 10.1161/CIRCRESAHA.113.280883. Epub 2013 Apr 19. PubMed PMID:23603512.



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