Mena/VASP and αII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy

Abstract

BackgroundIn 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.ResultsWe 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.ConclusionsTogether, 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.

A thioredoxin fold protein Sh3bgr regulates Enah and is necessary for proper sarcomere formation

“…As previously reported for the cardiac muscles (Benz et al, 2013), both confocal and super resolution SIM images clearly showed the Enah protein is also localized to the Z-line of somitic sarcomeres (Fig. S3E, 5A’).…”

“…During sarcomere assembly, the Enah protein localizes to the Z-line and is required for the α-II-spectrin and α-actin assembly at the Z-line of cardiac muscles and intercalated disc (ICD) in cardiomyocytes (Benz et al, 2013). Also, the Enah protein level is dramatically increased in the ICD and Z-line upon calsequestrin overexpression in mice (Aguilar et al, 2011).…”

“…Also, the Enah protein level is dramatically increased in the ICD and Z-line upon calsequestrin overexpression in mice (Aguilar et al, 2011). Loss of both Enah and Vasp in cardiomyocytes caused dilated cardiomyopathy which is due to the defective ICD and Z-line formation (Benz et al, 2013) and overexpression of Enah resulted in the exacerbation of heart failure after cardiac injury in mice (Belmonte et al, 2013). …”

Spectrin: Structure, function and disease

“…Vasodilator-stimulated phosphoprotein (VASP) [35] and Ena/VASP-like protein (EVL) [36], which are members of their namesake Ena/VASP family, play a key role during actin remodeling and pseudopodia extension during the activation of immune cells. In the heart, Ena/ VASP and II-spectrin assemble cardiac multiprotein complexes that regulate cytoplasmic actin networks [37]. These studies suggest that spectrin is crucial for cell adhesion and spreading.…”

Spectrin-based pathways underlying electrical and mechanical dysfunction in cardiac disease

“…Interestingly, several groups have identified involvement of spectrin in post-golgi targeting and long range transport of ion channel cargo to the membrane, although its specific role remains controversial [2, 23, 47, 48]. In a similar vein, exciting work has identified a spectrin-based complex involving Mena, VASP and α II -spectrin for regulating actin dynamics [49]. …”