Abstract
Increased atherosclerotic plaque formation can lead to lumen reduction and finally to lumen obstruction. Percutaneous transluminal angioplasty (PTA) or balloon angioplasty (dilation) are approaches generally used to treat coronary, but also peripheral atherosclerotic disease. Their goal is to restore the blood supply. The repair process or restructuring of the artery
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after balloon angioplasty comprises two major features, neointimal formation and geometrical remodeling, and results in a decreased lumen. In the process of atherosclerosis, and during neointimal formation and arterial remodeling, the structure of the arterial wall is changed dramatically. Collagen is one of the major components of the arterial wall, essential for arterial integrity, and therefore increased collagen synthesis and degradation are important processes.
Matrix metalloproteinases (MMPs) are key-enzymes responsible for collagen degradation, but also for cellular migration which is a well described feature in arterial remodeling. Broad spectrum inhibition of these MMPs revealed beneficial effects in the repair process after balloon dilation, but more specific inhibitors are needed due the side effects of these inhibitors. Next to their role in arterial remodeling, MMPs are also involved in atherosclerotic plaque progression. We need to understand arterial remodeling more in detail to be able to find new targets for intervention.
The first aim of our study was to explore the changes in collagen synthesis and degradation and the collagen content after balloon injury. We observed that collagen synthesis and degradation was increased and was associated with cell migration. We found that Hsp47, a protein essential for collagen synthesis, could be a potential new target for intervention.
In the second part of our study we focussed on the production and activation of the MMPs. We observed that the level of several MMPs were increased after balloon dilation, probably via a protein called extracellular matrix metalloproteinase inducer (EMMPRIN). Moreover, we observed that EMMPRIN forms were different between more unstable and stable atherosclerotic plaques. Therefore EMMPRIN might be a more specific target to intervene in arterial remodeling, but also for stabilization of the atherosclerotic plaque. Because EMMPRIN is an extracellular protein it is an attractive protein for intervention.
Finally, we studied the role of furin after dilation. Furin is a proprotein convertase and involved in the activation of several proteins, including some MMPs. Blocking furin activity prevents the activation of these MMPs, but also of TGF- β. We inhibited the activity of furin after balloon dilation which resulted in an inhibition of neointima formation.
Interventions on these different proteins could have beneficial effects for patients with cardiovascular problems by reducing restenosis rates and promoting plaque stability.
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