title: Myozap Deficiency Promotes Adverse Cardiac Remodeling via Differential Regulation of Mitogen-activated Protein Kinase/Serum-response Factor and β-Catenin/GSK-3β Protein Signaling.
abstract: The intercalated disc (ID) is a "hot spot" for heart disease, as several ID proteins have been found mutated in cardiomyopathy. Myozap is a recent addition to the list of ID proteins and has been implicated in serum-response factor signaling. To elucidate the cardiac consequences of targeted deletion of myozap in vivo, we generated myozap-null mutant (Mzp(-/-)) mice. Although Mzp(-/-) mice did not exhibit a baseline phenotype, increased biomechanical stress due to pressure overload led to accelerated cardiac hypertrophy, accompanied by "super"-induction of fetal genes, including natriuretic peptides A and B (Nppa/Nppb). Moreover, Mzp(-/-) mice manifested a severe reduction of contractile function, signs of heart failure, and increased mortality. Expression of other ID proteins like N-cadherin, desmoplakin, connexin-43, and ZO-1 was significantly perturbed upon pressure overload, underscored by disorganization of the IDs in Mzp(-/-) mice. Exploration of the molecular causes of enhanced cardiac hypertrophy revealed significant activation of β-catenin/GSK-3β signaling, whereas MAPK and MKL1/serum-response factor pathways were inhibited. In summary, myozap is required for proper adaptation to increased biomechanical stress. In broader terms, our data imply an essential function of the ID in cardiac remodeling beyond a mere structural role and emphasize the need for a better understanding of this molecular structure in the context of heart disease.
authors.affiliation: From the Department of Internal Medicine III, Molecular Cardiology and Angiology, and.
authors.forename: Ashraf Yusuf
authors.initials: AY
authors.lastname: Rangrez
authors.affiliation: From the Department of Internal Medicine III, Molecular Cardiology and Angiology, and.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eden
authors.affiliation: From the Department of Internal Medicine III, Molecular Cardiology and Angiology, and.
authors.forename: Reza
authors.initials: R
authors.lastname: Poyanmehr
authors.affiliation: From the Department of Internal Medicine III, Molecular Cardiology and Angiology, and.
authors.forename: Christian
authors.initials: C
authors.lastname: Kuhn
authors.affiliation: From the Department of Internal Medicine III, Molecular Cardiology and Angiology, and.
authors.forename: Katharina
authors.initials: K
authors.lastname: Stiebeling
authors.affiliation: From the Department of Internal Medicine III, Molecular Cardiology and Angiology, and.
authors.forename: Franziska
authors.initials: F
authors.lastname: Dierck
authors.affiliation: From the Department of Internal Medicine III, Molecular Cardiology and Angiology, and.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bernt
authors.affiliation: German Centre for Cardiovascular Research (DZHK, partner site Hamburg/Kiel/Lübeck), University Medical Center Schleswig-Holstein, Kiel D-24105, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.affiliation: the Anatomical Institute, Christian Albrechts University of Kiel, Kiel D-24098, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
authors.affiliation: the Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin 53233, and.
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchof
authors.affiliation: From the Department of Internal Medicine III, Molecular Cardiology and Angiology, and.
authors.forename: Derk
authors.initials: D
authors.lastname: Frank
authors.affiliation: From the Department of Internal Medicine III, Molecular Cardiology and Angiology, and norbert.frey@uk-sh.de.
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C511173:Mrtfa protein, mouse; C000594702:Mrtfa protein, rat; D009124:Muscle Proteins; C000594384:Myozap protein, mouse; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3
keywords: animal model; cadherin; cardiac development; cardiac hypertrophy; cardiac muscle; cardiomyocyte; cardiomyopathy; cardiovascular disease; heart; heart failure