Fight Aging!

Researchers here find an approach to selective upregulation of CXCR4 that acts to suppress the development of atherosclerosis in a mouse model. It is a small molecule treatment, so may well make its way into further development. Like all such treatments, however, it will likely prove to have little effect on established atherosclerotic plaques. It remains to be seen as to whether the research and development community can bring effective means of reversal of atherosclerosis to the clinic in the years ahead. Efforts to produce therapies capable of reversal have to date near all focused on enhancing reverse cholesterol transport, and subsequently failed in clinical trials. Meanwhile most new drug development in the cardiovascular field remains fixated on lowering LDL cholesterol in the bloodstream, an approach that cannot reverse existing plaque. New ways forward are much needed.

Researchers have in the past demonstrated that the transmembrane protein CXCR4 plays a significant role in the development of atherosclerosis. The protein transmits signals to the cell interior. If CXCR4 is specifically silenced in arterial endothelial cells or in smooth muscle cells, it results in more severe atherosclerotic lesions. At the same time, there is increased leukocyte ingress into the cell, which leads to inflammatory processes. With regard to leukocytes, however, the presence of CXCR4 can also promote the development of inflammatory processes.

The researchers therefore searched specifically for microRNA molecules that are limited to vascular cells and are involved in the regulation of CXCR4. And indeed, they managed to identify a good therapeutic starting point for the treatment of atherosclerosis in the form of miR-206, a candidate which occurs only in endothelial cells and in vascular smooth muscle cells. In those sites, it downregulates the expression of CXCR4 by binding to the transcripts of the CXCR4 gene and preventing their conversion into the protein.

For therapeutic application, the effect of miR-206 needs to be suppressed. To this end, the researchers developed a so-called target-site blocker: a molecule that specifically interrupts interactions between miR-206 and the CXCR4 transcripts and thus only boosts its expression in the respective cells. The researchers were able to demonstrate the effectiveness of this approach in a mouse model and in human cells in the culture. Most notably, the blocker they developed was able to prevent atherosclerosis in the mouse model.

Link: https://www.lmu.de/en/newsroom/news-overview/news/atherosclerosis-rna-fragment-creates-prospect-for-new-therapies.html