Abstract 11294: Cardiac-Restricted Overexpression of the Novel Intercalated Disc Protein Myozap Leads to a Protein Aggregate-Associated Cardiomyopathy
The intercalated disc (ID) is a major component of the cell-cell contact structures of cardiomyocytes ensuring their electro-mechanical coupling. During the last decade it became evident that the molecular components of the ID are critical regulators in the pathogenesis of inherited cardiac disease. We could recently identify and characterize a novel cardiac-enriched ID protein, termed Myozap, which interacts with several other ID proteins including desmoplakin. Mechanistically, it represents a positive modulator of the Rho-dependent SRF pathway linking the ID to gene regulation and actin dynamics. For further analyses of Myozap's function in vivo, we generated a mouse model with cardiac overexpression of Myozap cDNA (αMHC promoter). These mice developed significant cardiac hypertrophy (heart weight/tibia length +43%, p<0.01, n=8-10) as well as progressive LV dilation (LVEDD +20%, p<0.01). Consistently, Myozap-transgenic hearts displayed upregulation of the hypertrophic gene program (ANF 4.3-fold, p<0.001, and BNP 2.2-fold, p<0.01, n=7-9). Next, myozap transgenic animals were subjected to various forms of stress, including running exercise, which led to an accelerated cardiomyopathy with premature LV dysfunction and dilation. Moreover, chronic infusion of phenylephrine (PE) caused significant lethality in Myozap-Tg (n=5/8, p<0.05 vs. WT (1/7)). Unexpectedly, on the ultrastructural level, we could detect bulky aggregates containing Myozap, desmoplakin and other ID proteins. This aggregate-associated pathology closely resembled the changes in the hearts of patients suffering from desminopathies. Of note, desmin was not detectable in the aggregates of MyozapTG mice, but was displaced from the ID. In conclusion, cardiac overexpression of the novel ID protein Myozap leads to hypertrophy and cardiomyopathy, accompanied by protein aggregates and associated with sudden death upon PE treatment. Ongoing analyses of this transgenic model may help to understand the pathophysiology of protein aggregate-associated cardiomyopathies.
- © 2011 by American Heart Association, Inc.