Mice with cardiac-restricted overexpression of Myozap are sensitized to biomechanical stress and develop a protein-aggregate-associated cardiomyopathy.
The intercalated disc (ID) is a major component of the cell-cell contact structures of cardiomyocytes and has been recognized as a hot spot for cardiomyopathy. We have previously identified Myozap as a novel cardiac-enriched ID protein, which interacts with several other ID proteins and is involved in RhoA/SRF signaling in vitro. To now study its potential role in vivo we generated a mouse model with cardiac overexpression of Myozap. Transgenic (Tg) mice developed cardiomyopathy with hypertrophy and LV dilation. Consistently, these mice displayed upregulation of the hypertrophy-associated and SRF-dependent gene expression. Pressure overload (transverse aortic constriction, TAC) caused exaggerated cardiac hypertrophy, further loss of contractility and LV dilation. Similarly, a physiological stimulus (voluntary running) also led to significant LV dysfunction. On the ultrastructural level, Myozap-Tg mouse hearts exhibited massive protein aggregates composed of Myozap, desmoplakin and other ID proteins. This aggregate-associated pathology closely resembled the alterations observed in desmin-related cardiomyopathy. Interestingly, desmin was not detectable in the aggregates, yet was largely displaced from the ID. Molecular analyses revealed induction of autophagy and dysregulation of the unfolded protein response (UPR), associated with apoptosis. Taken together, cardiac overexpression of Myozap leads to cardiomyopathy, mediated, at least in part by induction of Rho-dependent SRF signaling in vivo. Surprisingly, this phenotype was also accompanied by protein aggregates in cardiomyocytes, UPR alteration, accelerated autophagy and apoptosis. Thus, this mouse model may also offer additional insight into the pathogenesis of protein-aggregate-associated cardiomyopathies and represents a new candidate gene itself.
Dept of Internal Medicine III (Cardiology and Angiology) UKSH, Campus Kiel, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Kiel, Germany. Electronic address: derk.frank@uksh.de.
Derk
D
Frank
Dept of Internal Medicine III (Cardiology and Angiology) UKSH, Campus Kiel, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Kiel, Germany.
Ashraf Y
AY
Rangrez
Dept of Internal Medicine III (Cardiology and Angiology) UKSH, Campus Kiel, Germany.
Reza
R
Poyanmehr
Dept of Molecular Hematology, University of Freiburg, Germany.
Thalia S
TS
Seeger
Dept of Internal Medicine III (Cardiology and Angiology) UKSH, Campus Kiel, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Kiel, Germany.
Christian
C
Kuhn
Dept of Internal Medicine III (Cardiology and Angiology) UKSH, Campus Kiel, Germany.
Matthias
M
Eden
Dept of Internal Medicine III (Cardiology and Angiology) UKSH, Campus Kiel, Germany.
Katharina
K
Stiebeling
Dept of Internal Medicine III (Cardiology and Angiology) UKSH, Campus Kiel, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Kiel, Germany.
Alexander
A
Bernt
Dept of Cell Biology, DKFZ, Heidelberg, Germany.
Christine
C
Grund
Dept of Cell Biology, DKFZ, Heidelberg, Germany.
Werner W
WW
Franke
Dept of Internal Medicine III (Cardiology and Angiology) UKSH, Campus Kiel, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Kiel, Germany. Electronic address: norbert.frey@uksh.de.
Norbert
N
Frey
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003893:Desmin / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000235:genetics*; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D056811:Unfolded Protein Response / Q000235:genetics; D020257:Ventricular Remodeling; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
D003893:Desmin; D009124:Muscle Proteins; C000594384:Myozap protein, mouse; D026362:Serum Response Factor; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
Cardiomyopathy; Intercalated disc; Protein aggregates; SRF; Transgenic mouse model