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1 Institut fur Klinische Biochemie und Pathobiochemie, Universitat Wuerzburg, Wuerzburg, Germany
2 Institut fur Pharmakologie und Toxikologie, Universitat Wuerzburg, Wuerzburg, Germany
3 Institut fur Pathologie, Charite, Berlin, Germany
4 Institut fur Anatomie, Universitat Wuerzburg, Wuerzburg, Germany
* To whom correspondence should be addressed. E-mail: hein{at}toxi.uni-wuerzburg.de.
Vasodilator-stimulated phosphoprotein (VASP) and mammalian enabled (Mena) are actin cytoskeleton and signaling modulators. Ena/VASP proteins share an identical domain organisation with an N-terminal EVH1 (Ena VASP homology) domain which mediates binding of these proteins to FPPPP-motif containing partners such as zyxin and vinculin. VASP and Mena are abundantly expressed in the heart. However, previous studies showed that disruption by gene-targeting of VASP or Mena genes in mice did not reveal any cardiac phenotype, whereas mice lacking both VASP and Mena died during embryonic development. In order to determine the in vivo function of Ena/VASP proteins in the heart, we used a dominant negative strategy with cardiac-specific expression of the VASP-EVH1 domain. Transgenic mice with cardiac myocyte-restricted, 
-myosin heavy chain (-MHC) promoter-directed expression of the VASP-EVH1 domain were generated. Overexpression of the EVH1 domain resulted in specific displacement of both VASP and Mena from cardiac intercalated discs. VASP-EVH1 transgenic mice developed dilated cardiomyopathy with myocyte hypertrophy and bradycardia which resulted in early postnatal lethality in mice with high levels of transgene expression. The results demonstrate that Ena/VASP proteins may play an important role in intercalated disc function at the interface between cardiac myocytes.
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