Abstract 1563: Cardiomyocyte-Specific Overexpression of Fas-Associated-Death-Domain Provokes a Dilated Cardiomyopathy
Fas-associated-death-domain (FADD) is a proapoptotic protein that plays a major role in intracellular cascades, downstream the pathway of Tumor-necrosis-factor-α and Fas-ligand, representing the most important ligands of the extrinsic apoptotic pathway. In contrast to previous models, this study performs intervention on intracellular pathway of the extrinsic cascade of apoptosis in cardiomyocytes for the very first time. We were able to generate stabile transgenic mice that expressed FADD specifically in the heart to receive a reproducible pattern of cardiomyocyte-specific FADD overexpression. At day 1 postpartum the lungs of Line 1 and 4 showed a significant increase in weight (p<0,05), Line 1 also from heart. The weight of the lungs did also significantly increase at day 14 postpartum in Line 1 and Line 5. Also the liver was affected, at least for the mice of Line 1. The left and right ventricular diameters were expanded, in Line 4 it was significantly at the day 1 postpartum. Ventricular wall thickness thus as the wall thickness of the septum were reduced. In the present study the cardiomyocyte-specific overexpression of FADD results in dilated ventricles with secondary congestion of the liver and the lung by forward and backward failure of the transgenic mice occurring early postpartum. Interestingly, apoptotic cardiomyocytes did not increase. Additionally, mice overexpressing the FADD transgene had interstitial leukocyte infiltrates in the heart. Six founder lines were produced and two of them (founders 2 and 4) died very early. All established founder lines demonstrated similar cardiac phenotype. The data suggest, that the FADD overexpression in cardiomyocytes leads to a dilated cardiomyopathy. Previous studies suspected that results like ours might be driven by cardiomyocytes, but were not able to provide evidence. However, our study demonstrates that the effects are just based on intracellular pathways. The proinflammatory reactions as well as the non increased apoptotic cell-rate are hints for alternative pathways and regulations, modulated by FADD in the cardiomyocyte.