Abstract 3832: Blocking of Frizzled-1/2 Receptors With UM206 Prevents Heart Failure and Improves Cardiac Function After Myocardial Infarction
Cardiovascular diseases are associated with activation of Wnt/Frizzled (Fzd) signaling. For example, our lab reported an upregulation of Fzd-1/2 expression after MI. However, the lack of specific low molecular weight ligands has hampered research on the functional role and therapeutic potential of the pathway. Based on regions with high homology between Wnt3a, 5a and 8a, we identified three peptides with antagonistic properties which we named UM206, UM207 and UM208. UM206 had an IC50=10−10M and 10−9M for Fzd-2 and -1, respectively. UM207 was less potent and UM208 was difficult to dissolve so we focused on UM206. In cardiac fibroblasts immortalized with telomerase, UM206 (1.10−8M) completely blocked the inhibitory effects of Wnt3a on migration and differentiation. Subsequently we tested UM206 in a mouse model of MI. Plasma half life was 90 minutes. Administration of UM206 to infarcted mice by osmotic minipump (6μg/kg.hr) for 14 days showed beneficial effects in infarct healing: 50% reduction in infarct area, associated with a 5-fold increase (p<0.001) in myofibroblast numbers compared to untreated mice. Moreover, the collagen content was significantly decreased after UM206 treatment in comparison to control. Cardiac function, however, was unaffected. Therefore, we repeated the experiment but prolonged the treatment to 5 weeks. UM206 treatment completely prevented death due to heart failure, which started to occur after 2 weeks in the untreated group. This study also revealed significant improvement of the EDV (0.21+/−0.02 cm3 untreated to 0.13+/−0.03 cm3 treated, p<0.05) and EF (16.5+/−0.2 % and 31.4+/−0.4 %, p<0.05) and hemodynamic parameters like +dp/dt and −dp/dt were also significantly improved. The amount of myofibroblasts still was 2-fold higher in 5 week treated versus non-treated mice. Furthermore, total collagen was still significantly lower in the treated animals. In conclusion, UM206, the first low molecular weight frizzled-1/2 antagonist, has beneficial effects on infarct healing and prevents heart failure by increasing myofibroblast numbers in the infarcted area which counteracts dilatation. This underscores the importance Fzd-1 and -2 as novel therapeutic target in cardiovascular diseases.