Background: Myozap is a new addition to the list of intercalated disc (ID) proteins, which we previously identified using a bioinformatics screen. In vitro characterization of Myozap revealed that it activates Rho-dependent SRF signaling. Moreover, cardiac restricted overexpression of Myozap in mice resulted in protein aggregate-associated cardiomyopathy, whereas, knockdown of its ortholog in Zebrafish led to severe contractile dysfunction and cardiomyopathy. The objective of the current study was to elucidate the cardiac consequences of targeted deletion of Myozap in mice.
Methods and Results: We generated a Myozap null mutant (MZP-ko) by global deletion of Myozap in mice. Unchallenged MZP-ko mice did not exhibit a baseline cardiac phenotype. However, upon biomechanical stress due to TAC (transverse aortic constriction), deficiency for Myozap led to accelerated cardiac hypertrophy (significant increases in the heart to body weight, left ventricular to body weight ratios) and fibrosis, accompanied by “super”-induction of the hypertrophic gene program (ANF/BNP). Moreover, MZP-ko mice revealed a severe reduction of fractional shortening and signs heart failure (increased lung/body weights) as well as a markedly increased mortality in response to TAC). Additional molecular data exhibited a significant decrease in the levels of native and phosphorylated Connexin 43 after transverse aortic constriction (TAC) in MZP-ko mice compared to wildtype animals. Finally, we observed a downregulation of dysbindin, a novel interaction partner of Myozap and known inducer of ERK1/2 signaling in TAC operated MZP-ko mice. Consistently, activation of ERK1/2 in response to TAC was blunted compared to wild-type littermates.
Conclusions: We here show that myozap deficiency in vivo leads to a maladaptative response to increased biomechanical stress associated with cardiomyopathy, heart failure and cardiac death. Mechanistically, this phenotype can at least in part be explained by the interruption of the interaction between myozap and dysbindin with subsequent loss of ERK1/2 activation. Taken into a larger perspective, our data imply an essential role of the ID and its associated proteins in cardiac remodeling.