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Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy
Shimako Yamamoto, … , Stephen F. Vatner, Junichi Sadoshima
Shimako Yamamoto, … , Stephen F. Vatner, Junichi Sadoshima
Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1463-1474. https://doi.org/10.1172/JCI17459.
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Categories: Article Cardiology

Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy

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Abstract

Activation of mammalian sterile 20–like kinase 1 (Mst1) by genotoxic compounds is known to stimulate apoptosis in some cell types. The importance of Mst1 in cell death caused by clinically relevant pathologic stimuli is unknown, however. In this study, we show that Mst1 is a prominent myelin basic protein kinase activated by proapoptotic stimuli in cardiac myocytes and that Mst1 causes cardiac myocyte apoptosis in vitro in a kinase activity–dependent manner. In vivo, cardiac-specific overexpression of Mst1 in transgenic mice results in activation of caspases, increased apoptosis, and dilated cardiomyopathy. Surprisingly, however, Mst1 prevents compensatory cardiac myocyte elongation or hypertrophy despite increased wall stress, thereby obscuring the use of the Frank-Starling mechanism, a fundamental mechanism by which the heart maintains cardiac output in response to increased mechanical load at the single myocyte level. Furthermore, Mst1 is activated by ischemia/reperfusion in the mouse heart in vivo. Suppression of endogenous Mst1 by cardiac-specific overexpression of dominant-negative Mst1 in transgenic mice prevents myocyte death by pathologic insults. These results show that Mst1 works as both an essential initiator of apoptosis and an inhibitor of hypertrophy in cardiac myocytes, resulting in a previously unrecognized form of cardiomyopathy.

Authors

Shimako Yamamoto, Guiping Yang, Daniela Zablocki, Jing Liu, Chull Hong, Song-Jung Kim, Sandra Soler, Mari Odashima, Jill Thaisz, Ghassan Yehia, Carlos A. Molina, Atsuko Yatani, Dorothy E. Vatner, Stephen F. Vatner, Junichi Sadoshima

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Figure 5

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(a) Immunoblot analyses of heart homogenates with anti-myc Ab (upper pan...
(a) Immunoblot analyses of heart homogenates with anti-myc Ab (upper panel). Note that Myc-Mst1 migrates at 62 kDa. Immunoblots were also conducted using anti-human Mst1 Ab (lower panel). (b) Tissue homogenates were prepared from various organs of Tg-Mst1. Immunoblot analyses were performed with anti-myc Ab. (c) Heart homogenates were prepared from Tg-Mst1 or nontransgenic control mice (NTg). In-gel MBP kinase assays were performed. n = 3. (d and e) Gross appearance and a transverse section of the hearts obtained from Tg-Mst1 and NTg. In e, hematoxylin-eosin staining was performed (96 days). (f) A photograph of the liver isolated from Tg-Mst1 and littermate NTg (96 days). (g) Hematoxylin-eosin staining of the lung.
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