Abstract 17437: Transgenic Mice Overexpressing the ID Protein Myozap Are Sensitized to Pressure Overload and Develop a Progressive Protein-aggregate Associated Cardiomyopathy
The intercalated disc (ID) is an important component of the cell contact structures of cardiomyocytes establishing electro-mechanical coupling. In recent work, we could describe Myozap, a novel ID protein, which interacts with a subset of other ID proteins.
Here we show that overexpression of Myozap activates the Rho-dependent SRF pathway in cardiomyocytes. In line with these results, RNAi-mediated Myozap knockdown blocked Rh-/SRF-activation connecting the ID to gene expression and actin dynamics.
For further analyses of Myozap’s functions in vivo, we generated a mouse model with αMHC-driven cardiac overexpression of Myozap. 1 y old mice developed cardiomyopathy with significant hypertrophy (heart weight/tibia length +43%, p<0.01, n=8-10) as well as LV dilation (LVEDD +20%, p<0.01) and a trend towards LV dysfunction (fractional shortening (FS) 50% vs. 42%, n=10, p=0.07). Consistently, these mice displayed upregulation of the fetal gene program (nppa 4.3x, p<0.001, nppb 2.2x, p<0.01, n=7-9). Voluntary running led to accelarated cardiomyopathy in young mice with premature LV dysfunction and dilation.
Ultrastructurally, we could detect dose-dependent protein aggregates containing Myozap, desmoplakin and other ID proteins. These aggregates appeared to be highly similar to myocardial changes found in desminopathies. However, desmin was not detectable in the aggregates in MyozapTG mice, but appeared to be displaced from the ID. Detailed molecular analyses also revealed dysregulation of typical members of the unfolded protein response (UPR) associated with upregulation of UPR-related apoptosis.
Pressure overload via transverse aortic constriction (TAC) caused exaggerated hypertrophy (heart/body weight 7.9 mg/g in Myozap TG-TAC vs. 5.6 mg/g in WT-TAC, n=11 each, p=0.002) and pronounced LV dysfunction (FS 15.3% Myozap TG-TAC vs. 33.0% WT-TAC, n=11 each, p<0.001).
Taken together, overexpression of Myozap activates RhoA-dependent signaling and leads to hypertrophy and cardiomyopathy in mice, which is worsened by pressure overload. The phenotype is accompanied by protein aggregates, UPR alteration and apoptosis. Therefore, Myozap overexpression offers new insights in the pathogenesis of protein aggregate-associated cardiomyopathies.
- © 2013 by American Heart Association, Inc.