Disruption of cardiac Ena-VASP protein localization in intercalated disks causes dilated cardiomyopathy.
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.
Eigenthaler
Martin
M
Institut für Klinische Biochemie und Pathobiochemie, Universität Würzburg, Germany.
Engelhardt
Stefan
S
Schinke
Birgitta
B
Kobsar
Anna
A
Schmitteckert
Eva
E
Gambaryan
Stepan
S
Engelhardt
Catherine M
CM
Krenn
Veit
V
Eliava
Marina
M
Jarchau
Thomas
T
Lohse
Martin J
MJ
Walter
Ulrich
U
Hein
Lutz
L
D000818:Animals; D001919:Bradycardia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D016277:Ventricular Function, Left; D000098662:Vasodilator-Stimulated Phosphoprotein
D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; C102176:Enah protein, mouse; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein