Abstract 18420: Myozap-deficiency Inhibits SRF Signaling and Causes Severe Cardiomyopathy in Response to Pathological Biomechanical Stress in vivo
Background: We recently showed that the intercalated disc (ID) protein Myozap activates Rho-dependent SRF signaling both in vitro, and in vivo. Conversely, knockdown of its ortholog in Zebrafish led to severe contractile dysfunction and cardiomyopathy.
Methods and Results: We generated a Myozap null mutant (MZP-ko) by global deletion of Myozap in mice. The absence of Myozap caused neither structural defects nor a baseline cardiac phenotype and led only to mild cardiac hypertrophy upon aging. Of note, induction of SRF target genes and the activation of SRF per se were markedly inhibited in MZP-ko mice. Nevertheless, biomechanical stress induced by transverse aortic constriction (TAC) triggered an excessive increase in cardiac hypertrophy (43% or 36% increased heart wt:body wt or LV wt:body wt ratios, p<0.001), an increased cell surface area, as well as accelerated fibrosis, followed by “super”- induction of the hypertrophic gene program (ANF/BNP). Moreover, MZP-ko mice revealed a severe reduction of fractional shortening (average %FS for MZP-ko 14.5% compared to 33.5% for wild-type littermates, p<0.001) and clinical signs of heart failure (54% increase in lung/body weights, p<0.001) which also caused a profound increase in mortality in response to TAC. Furthermore, expression of other ID proteins like N-Cadherin, Desmoplakin and Connexin 43 was found significantly altered upon pressure overload in MZP-ko mice. 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 was blunted in MZP-ko mice after TAC.
Conclusions: We here show that myozap deficiency in vivo inhibits SRF- and ERK1/2-signaling leading to a maladaptative response to increased biomechanical stress, followed by cardiomyopathy, heart failure and cardiac death. Moreover, myozap deficiency severely altered the expression of its direct ID interaction partners such as Dysbindin and Desmoplakin. In a broader perspective, our data identify signaling at the level of the intercalated disc as a critical component of cardiac remodeling.
Author Disclosures: A.Y. Rangrez: None. D. Frank: None. R. Poyanmehr: None. A. Bernt: None. M. Eden: None. C. Kuhn: None. N. Frey: None.
- © 2014 by American Heart Association, Inc.