Actin Binding GFP Allows 4D In Vivo Imaging of Myofilament Dynamics in the Zebrafish Heart and the Identification of Erbb2 Signaling as a Remodeling Factor of Myofibril Architecture

Circulation Research - Tập 115 Số 10 - Trang 845-856 - 2014
Sven Reischauer1,2, Rima Arnaout1,2, Radhan Ramadass1,2, Didier Y. R. Stainier1,2
1Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.R., R.R., D.Y.R.S.).
2From the Department of Biochemistry and Biophysics (S.R., D.Y.R.S.) and Division of Cardiology, Department of Medicine, Cardiovascular Research Institute (R.A.), University of California, San Francisco; and Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.R., R.R., D.Y.R.S.).

Tóm tắt

Rationale : Dilated cardiomyopathy is a leading cause of congestive heart failure and a debilitating complication of antineoplastic therapies. Despite disparate causes for dilated cardiomyopathy, maladaptive cardiac remodeling and decreased systolic function are common clinical consequences, begging an investigation of in vivo contractile dynamics in development and disease, one that has been impossible to date. Objective : To image myocardial contractile filament dynamics in vivo and to assess potential causes of dilated cardiomyopathy in antineoplastic therapies targeting the epidermal growth factor receptor Erbb2. Methods and Results : We generated a transgenic zebrafish line expressing an actin-binding green fluorescent protein in cardiomyocytes, allowing an in vivo imaging of myofilaments. Analysis of this line revealed architectural differences in myofibrils of the distinct cardiomyocyte subtypes. We used this model to investigate the effects of Erbb2 signaling on myofibrillar organization because drugs targeting ERBB2 (HER2/NEU) signaling, a mainstay of breast cancer chemotherapy, cause dilated cardiomyopathy in many patients. High-resolution in vivo imaging revealed that Erbb2 signaling regulates a switch between a dense apical network of filamentous myofibrils and the assembly of basally localized myofibrils in ventricular cardiomyocytes. Conclusions : Using this novel line, we compiled a reference for myofibrillar microarchitecture among myocardial subtypes in vivo and at different developmental stages, establishing this model as a tool to analyze in vivo cardiomyocyte contractility and remodeling for a broad range of cardiovascular questions. Furthermore, we applied this model to study Erbb2 signaling in cardiomyopathy. We show a direct link between Erbb2 activity and remodeling of myofibrils, revealing an unexpected mechanism with potentially important implications for prevention and treatment of cardiomyopathy.

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Tài liệu tham khảo

10.1093/oxfordjournals.eurheartj.a015092

Baselga J. Current and planned clinical trials with trastuzumab (Herceptin). Semin Oncol. 2000;27:27–32.

10.1186/1750-1172-1-27

10.1111/cts.12116

10.1038/nrcardio.2013.105

10.1038/nm0502-459

10.1073/pnas.122249299

10.1016/j.tcb.2005.12.001

10.1038/nmeth.1220

10.1128/MCB.22.13.4714-4722.2002

10.1038/ncb0901-785

10.4161/cam.22123

10.1038/nrm1962

10.1126/science.2470152

10.1186/1756-8722-6-38

10.1038/378390a0

10.1038/378394a0

10.1242/dev.098632

10.1242/dev.053736

10.1056/NEJM200103153441101

10.1007/978-1-60327-019-9_3

10.1128/MCB.11.3.1454

10.1016/j.cub.2005.02.030

10.1016/j.cub.2003.11.055

10.1242/dev.082586

10.1117/1.2061567

10.1371/journal.pgen.1000720

10.1093/bioinformatics/bth254

10.1038/nprot.2013.041

10.1038/ng875

10.1016/0012-1606(92)90094-W

10.1002/dvdy.22526

10.1161/01.cir.0000013839.41224.1c

10.1074/jbc.M308033200

10.1016/j.yjmcc.2003.09.012

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Circulation Research

Tập 115 Số 10

845-856

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