Abstract
Vasodilator-stimulated phosphoprotein (VASP) and mammalian enabled
(Mena) are actin cytoskeleton and signaling modulators. Ena-VASP
proteins share an identical domain organization with an NH2-terminal
Ena VASP homology (EVH1) domain, which mediates the 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. 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,
alpha-myosin heavy chain 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
disks. 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 disk function at the interface between cardiac
myocytes.
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