The Atheroprotective Effects of Disrupting a Cell-Specific miRNA-CXCR4 Interaction in Mice – Insights from Nature Reviews Cardiology
Atherosclerosis, a chronic inflammatory disease characterized by the accumulation of lipid-rich plaques in the arterial walls, is a leading cause of cardiovascular diseases such as heart attacks and strokes. Despite significant advancements in understanding the pathogenesis of atherosclerosis, effective therapeutic strategies to prevent or treat this condition remain limited. However, recent research published in Nature Reviews Cardiology has shed light on a potential novel approach to combat atherosclerosis by disrupting a cell-specific microRNA (miRNA)-CXCR4 interaction.
MicroRNAs are small non-coding RNA molecules that play a crucial role in post-transcriptional gene regulation. They bind to messenger RNA (mRNA) molecules and inhibit their translation into proteins, thereby modulating gene expression. Dysregulation of miRNAs has been implicated in various diseases, including atherosclerosis. In this context, miR-146a has emerged as a key player in the development and progression of atherosclerosis.
The study highlighted in Nature Reviews Cardiology demonstrates that miR-146a promotes atherosclerosis by targeting the chemokine receptor CXCR4. CXCR4 is expressed on various cell types, including endothelial cells, smooth muscle cells, and immune cells, and plays a crucial role in inflammation and immune cell recruitment during atherosclerosis. The researchers found that miR-146a directly binds to the 3′ untranslated region (UTR) of CXCR4 mRNA, leading to its degradation and subsequent reduction in CXCR4 expression.
To investigate the therapeutic potential of disrupting the miR-146a-CXCR4 interaction, the researchers generated mice with a specific deletion of miR-146a in endothelial cells. These mice were then subjected to a high-fat diet to induce atherosclerosis. Remarkably, the deletion of miR-146a in endothelial cells resulted in a significant reduction in atherosclerotic plaque formation compared to control mice. This finding suggests that targeting the miR-146a-CXCR4 axis specifically in endothelial cells could be a promising strategy to prevent or treat atherosclerosis.
Further analysis revealed that the atheroprotective effects of miR-146a deletion in endothelial cells were mediated by increased expression of CXCR4 and subsequent inhibition of endothelial inflammation. The researchers observed reduced adhesion molecule expression and decreased recruitment of inflammatory cells to the arterial walls in miR-146a-deficient mice. These findings highlight the critical role of endothelial cell-specific miR-146a in regulating vascular inflammation and atherosclerosis.
The study also investigated the therapeutic potential of targeting miR-146a in established atherosclerosis. The researchers utilized locked nucleic acid (LNA) antisense oligonucleotides to inhibit miR-146a activity in a mouse model with pre-existing atherosclerotic plaques. Treatment with LNA antisense oligonucleotides resulted in a significant reduction in plaque size and improved plaque stability, suggesting that targeting miR-146a could be a viable therapeutic strategy for treating advanced atherosclerosis.
Overall, the study published in Nature Reviews Cardiology provides valuable insights into the atheroprotective effects of disrupting a cell-specific miRNA-CXCR4 interaction. Targeting miR-146a specifically in endothelial cells holds promise as a novel therapeutic approach to prevent or treat atherosclerosis. Further research is needed to explore the safety and efficacy of this strategy in human subjects. Nonetheless, these findings open up new avenues for developing miRNA-based therapies for cardiovascular diseases, offering hope for improved outcomes for patients with atherosclerosis.
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