| Myocardial infarction is a frequent cardiovascular event in the Western world, and one of the leading causes of the development of heart failure. This is due to the dilatation of the infarcted heart, which in turn is the result of inadequate wound healing in the infarct area. The present proposal aims at improvement of this wound healing process by intervening in the myofibroblasts numbers and characteristics in the infarct area. These cells not only can deposit extracellular matrix components, but also have contractile properties that can be assumed to prevent infarct dilatation. The central hypothesis of this proposal is that heart failure after MI can be prevented by reinforcement of the scar that is formed in the infarct area, by increasing the number and optimizing the characteristics of myofibroblasts. To test this hypothesis we will intervene in the differentiation of fibroblasts into myofibroblasts. In the second part of this project we will modulate the numbers of (myo)fibroblasts in the infarct area by either inhibiting proliferation or blocking apoptosis of these cells. The third part of this project addresses the architectural control of the infarct healing. When the infarct healing is studied in detail, a striking level of organization, both in time and space, becomes apparent. In previous research, we have observed the expression of members of a cascade that controls the architectural organization of cells, the Wnt/frizzled/dishevelled cascade. Interventions in this cascade will be executed to study the importance of this cascade in myofibroblast alignment and organization during infarct healing. The overall aim of this proposal is to define targets that can be used for therapeutic interventions in infarct healing, to prevent the cardiac dilatation that leads to the development of heart failure after myocardial infarction. |
