ECM and Wnt signaling

A major research focus of this program is the wound healing process after myocardial infarction. Recently we have obtained more information on the role of the myofibroblast in infarct healing. Myofibroblasts are differentiated fibroblasts that combine the synthetic properties of fibroblasts with the contractile properties of smooth muscle cells. They are abundantly present in well-healed human infarcts where they are thought to repair the wear and tear of the extracellular matrix. This prevents dilatation of the scar tissue, whichwould lead to the development of heart failure. We have studied the infarct healing in 5 different mouse strains and found a correlation between myofibroblast content, dilatation of the infarct area and cardiac function. Moreover, we have found a novel pathway, the Wnt/frizzled pathway, to control myofibroblast differentiation. In a frizzled-2 knockout mouse, developed in our lab, we observed improved infarct healing and better cardiac function after infarction. Inspired by the success of spironolacton therapy in heart failure, we also focus on novel ways to inhibit aldosterone effects during cardiac remodeling. This has led to the development of Moeras 115, an aldosterone synthase inhibitor which prevents fibrosis during cardiac remodeling in rats.
Another development in this program is the identification of novel biomarkers for cardiac remodeling. Such biomarkers would allow the identification of heart failure-prone patients before clinical symptoms become manifest. At present, we are involved in the identification of circulating biomarkers for the inflammation that is associated with heart failure development. We are also working on molecular imaging agents that will allow the monitoring of the myofibroblast content in the infarct area which may serve as early predictor for dilatation of the infarcted heart, one of the main causes of heart failure.

The researchers that are active in this program all have a pharmacological background. This allows them to develop compounds that can bind to targets relevant in cardiac remodeling and modulate their activity. A nice example is the recent development of a high affinity antagonist for the frizzled-1 and -2 receptor, UM206. A 5 week administration of UM206, starting after induction of myocardial infarction, stimulated myofibroblast differentiation in the infarcted mouse heart. This resulted in less dilatation of the infarct and a betterpump function of the heart. Moreover, a complete prevention of heart failure was achieved, underscoring the importance of the Wnt/frizzled pathway as a novel therapeutic target in cardiovascular disease. A publication in which these findings are described is currently under review at Circulation.