Research project
Therapeutic intervention to enhance atherosclerotic plaque stability
Proteases degrade matrix molecules in the atherosclerotic plaque, thereby reducing atherosclerotic plaque stability. Mast cells, that contain proteases such as tryptase and chymase, have been identified at the site of rupture in specimens of human coronary arteries and their number in the plaque was seen to be predictive for future cardiovascular events. We have shown that episodes of systemic mast cell activation, during plaque progression in mice, leads to robust plaque expansion, while inhibition of chymase enhances plaque stability.
- Contact
- Ilze Bot
Acute cardiovascular syndromes such as myocardial infarction and stroke are generally caused by rupture of an atherosclerotic plaque. Plaque rupture may be prevented by increasing the stability of the atherosclerotic plaque. In this research theme we aim to identify target proteins or cells that actively contribute to plaque destabilization. We have in the past shown that deficiency of cathepsin K or cathepsin S in leukocytes leads to decreased collagen and less elastic lamina fragmentation, establishing that these cathepsins play a critical role in plaque stability.
The mast cell, a potent immune effector cell type mainly recognized for its role in allergy and asthma, has been observed in human atherosclerotic plaques as well as in the perivascular tissue during atherosclerotic plaque progression. It was recently shown that intraplaque mast cell numbers are of predictive value for future cardiovascular events in patients. We showed that activation of perivascular mast cells in advanced plaques resulted in decreased plaque stability. Inhibition of chymase, one of the most potent mast cell proteases, resulted in reduced plaque size and increased plaque stability. Recently, we have also established that inhibition of the miRNA 494 during atherosclerotic lesion development inhibited disease progression and resulted in more stable plaques.
In this research theme, we aim to develop novel therapeutic strategies to increase plaque stability and to reduce the incidence of acute cardiovascular events.