Key result
Myo6 null mutation in mice drives significant LVH, cardiopulmonary fibrosis, and abnormal vascular ultrastructure.
The Snell's waltzer mouse model demonstrates that loss of myosin VI function leads to left ventricular hypertrophy, fibrosis, and vascular endothelial cell defects, independent of its role in arterial development.
Myo6-null mice implicate myosin VI in cardiac hypertrophy and fibrosis; hypothesis-generating for human disease.
In mice and humans, loss of myosin VI (Myo6) function results in deafness, and certain Myo6 mutations also result in cardiomyopathies in humans. The current studies have utilized the Snell's waltzer (sv) mouse (a functional null mutation for Myo6) to determine if this mouse also exhibits cardiac defects and thus used to determine the cellular and molecular basis for Myo6-associated heart disease. Myo6 is expressed in mouse heart where it is predominantly expressed in vascular endothelial cells (VECs) based on co-localization with the VEC cell marker CD31. Sv/sv heart mass is significantly greater than that of sv/+ littermates, a result of left ventricle hypertrophy. The left ventricle of the sv/sv exhibits extensive fibrosis, both interstitial and perivascular, based on histologic staining, and immunolocalization of several markers for fibrosis including fibronectin, collagen IV, and the fibroblast marker vimentin. Myo6 is also expressed in lung VECs but not in VECs of intestine, kidney, or liver. Sv/sv lungs exhibit increased periaveolar fibrosis and enlarged air sacs. Electron microscopy of sv/sv cardiac and lung VECs revealed abnormal ultrastructure, including luminal protrusions and increased numbers of cytoplasmic vesicles. Previous studies have shown that loss of function of either Myo6 or its adaptor binding partner synectin/GIPC results in impaired arterial development due to defects in VEGF signaling. However, examination of synectin/GIPC-/- heart revealed no fibrosis or significantly altered VEC ultrastructure, suggesting that the cardiac and lung defects observed in the sv/sv mouse are not due to Myo6 function in arterial development.
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Hegan et al. (2015) studied Myo6-associated heart disease / cardiomyopathy. Myo6 null mutation (Snell's waltzer sv/sv) vs. sv/+ littermates was evaluated on Cardiac and pulmonary defects (hypertrophy, fibrosis, VEC ultrastructure). Snell's waltzer mice with a Myo6 null mutation exhibited significant left ventricular hypertrophy, extensive cardiac and pulmonary fibrosis, and abnormal vascular endothelial cell ultrastructure.
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