A new therapeutic approach for atherosclerosis: the role of CXCR4 & microRNA
This is a summary of Ismail Çimen, Lucia Natarelli, Zahra Abedi Kichi, James M. Henderson, Floriana M.Farina, Eva Briem, Maria Aslani, (…), Donato Santovito, Christian Weber: Targeting a cell-specific microRNA repressor of CXCR4 ameliorates atherosclerosis in mice (2023). https://doi.org/10.1126/scitranslmed.adf3357, which appeared in Science Translational Medicine.
Atherosclerosis, a thickening or hardening of the arteries by plaques, is considered a frequent cause of cardiovascular diseases and strokes. Some time ago, we discovered that the transmembrane protein CXCR4 plays a significant role in its development by transmitting signals to the cell interior. We found that if CXCR4 is silenced in the arterial endothelial or smooth muscle cells, the atherosclerotic lesions worsen. Whereas concerning leukocytes, we found the opposite effect: CXCR4 presence leads to more inflammation. Therefore, to counteract atherosclerosis, we wanted to boost the expression of CXCR4 on the vascular wall only, not on the leukocytes, without influencing any other biological process. We, therefore, searched for microRNA molecules that are limited to vascular cells and are involved in the regulation of CXCR4.
Using databases, molecular biological screening in cell cultures, and mouse models we found a good candidate: miR-206. This microRNA occurs only in endothelial cells and in vascular smooth muscle cells where 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. Therefore, we developed a so-called target-site blocker (TSB): a molecule that specifically interrupts interactions between miR-206 and the CXCR4 transcripts and thus only boosts its expression in the respective cells.
We demonstrated the effectiveness of the target-site blocker: it increased CXCR4 in vascular cells in cell cultures. Moreover, it was able to prevent atherosclerosis in the mouse model.
We showed that our approach is a potential therapeutic approach that could be used to treat atherosclerosis and other vascular diseases. Eliminating microRNA-mediated gene suppression represents an attractive, feasible, and cost-effective method for fine-tuning gene expression at the cell-specific level.
This research was led by Christian Weber from SyNergy together with Donato Santovito from LMU. They plan to evaluate their results in preclinical studies with larger animal models within the framework of the German Cardiovascular Research Centre (DZHK) and the Cluster for Nucleic Acid Therapeutics Munich (CNATM), and last but not least within the DFG Excellence Cluster SyNergy, where therapeutic applicability to stroke models and neuroprotective effects will be explored.