Myozap Deficiency Promotes Adverse Cardiac Remodeling via Differential Regulation of Mitogen-activated Protein Kinase/Serum-response Factor and β-Catenin/GSK-3β Protein Signaling

• DOI: 10.1074/jbc.m115.689620
• Publication Date: 2015-12-31T03:43:34Z
• Authors: Ashraf Yusuf Rangrez; Matthias Eden; Reza Poyanmehr; Christian Kuhn; Katharina Stiebeling; Franziska Dierck; Alexander Bernt; Renate Lüllmann-R...; Hartmut Weiler; Paulus Kirchof; Derk Frank; Norbert Frey
• Keywords: ASK1

The intercalated disc (ID) is a "hot spot" for heart disease, as several ID proteins have been found mutated in cardiomyopathy. Myozap recent addition to the list of and has implicated serum-response factor signaling. To elucidate cardiac consequences targeted deletion myozap vivo, we generated myozap-null mutant (Mzp(-/-)) mice. Although Mzp(-/-) mice did not exhibit baseline phenotype, increased biomechanical stress due pressure overload led accelerated hypertrophy, accompanied by "super"-induction fetal genes, including natriuretic peptides A B (Nppa/Nppb). Moreover, manifested severe reduction contractile function, signs failure, mortality. Expression other like N-cadherin, desmoplakin, connexin-43, ZO-1 was significantly perturbed upon overload, underscored disorganization IDs Exploration molecular causes enhanced hypertrophy revealed significant activation β-catenin/GSK-3β signaling, whereas MAPK MKL1/serum-response pathways were inhibited. In summary, required proper adaptation stress. broader terms, our data imply an essential function remodeling beyond mere structural role emphasize need better understanding this structure context disease.