microRNA could offer a safe target in atherosclerosis

Researchers led by Wolfgang Enard from LMU Munich have identified a microRNA-based mechanism that drives atherosclerosis by weakening the integrity of blood vessel walls.

The researcher demonstrateded that targeting of miR-206-3p with an experimental compound safely reversed the onset of atherosclerosis in a mouse model, hinting that similar strategies could fill the need for new therapies for this widespread chronic condition.

Atherosclerosis is a major risk factor for the development of heart attacks and stroke, and has become one of the world’s leading causes of death globally. Searching for new therapies, companies have attempted to treat atherosclerosis by supporting the action of the chemokine receptor CXCR4, which promotes re-endothelialisation. However, CXCR4 is difficult to target because it’s also expressed in other types of cells, which leads to off-target effects and treatment toxicity.

Now, Christian Weber and colleagues tackled this safety roadblock by targeting a pathway that represses CXCR4 specifically in blood vessels. The team from LMU Munich and the University of Maastricht examined human and mouse endothelial cells and vascular smooth muscle cells, finding that a microRNA named miR-206-3p repressed CXCR4’s activity in the cells. The researchers then treated mice with a compound code-named CXCR4-TSB that prevents miR-206-3p from interacting with CXCR4 specific to blood vessels.

This target-site blocker boosted the expression of the cxcr4 gene, reduced the permeability of blood vessels, and prevented diet-induced atherosclerosis in the animals. Weber et al. also observed that plaque specimens from patients with atherosclerosis harboured less CXCR4 and more miR-206-3p as the disease progressed, suggesting this microRNA could also offer a target in humans.