Mena/VASP and αII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy.
BACKGROUND
In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks.


RESULTS
We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired.


CONCLUSIONS
Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities.
Institute of Physiology I, University of Würzburg, D-97070 Würzburg, Germany. benz@vrc.uni-frankfurt.de
Peter M
PM
Benz
Carla J
CJ
Merkel
Kristin
K
Offner
Marco
M
Abeßer
Melanie
M
Ullrich
Tobias
T
Fischer
Barbara
B
Bayer
Helga
H
Wagner
Stepan
S
Gambaryan
Jeanine A
JA
Ursitti
Ibrahim M
IM
Adham
Wolfgang A
WA
Linke
Stephan M
SM
Feller
Ingrid
I
Fleming
Thomas
T
Renné
Stefan
S
Frantz
Andreas
A
Unger
Kai
K
Schuh
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D006329:Heart Conduction System / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D013049:Spectrin / Q000737:chemistry / Q000378:metabolism*; D018909:src Homology Domains; D000098662:Vasodilator-Stimulated Phosphoprotein
D000199:Actins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; C102176:Enah protein, mouse; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D013049:Spectrin