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

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

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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(a–g) Cardiac myocytes were transduced with adenovirus harboring either ...
(a–g) Cardiac myocytes were transduced with adenovirus harboring either wild-type Mst1 (AdX-Mst1), AdX-DN-Mst1, or control adenovirus (Ad5 βgal) at indicated concentrations. Myocytes were harvested 48 h after transduction. Some myocytes (c and f) were treated with a caspase-3 inhibitor (DEVD-CHO, 100 μM). (a and b) Immunoblot analyses were performed using anti-Mst1 polyclonal Ab. Cont, control, where no virus was applied. n = 4. (c) In-gel MBP kinase assays were performed. n = 5. (d) The effect of adenovirus transduction (30 MOI) upon the morphology of cardiac myocytes is shown. Note that cell death with shrinkage is observed in AdX-Mst1–transduced cardiac myocytes. n = 5. (e and f) Cytoplasmic accumulation of mono- and oligo-nucleosomes, a sensitive indicator of DNA fragmentation by apoptosis, was quantitated by Cell Death ELISA Plus. (e) Myocytes were transduced with indicated doses of either control virus, AdX-Mst1, or AdX-DN-Mst1. The experimental data are normalized by those obtained in control myocytes without adenovirus transduction. n = 3. (f) Myocytes were transduced with AdX-Mst1 (10 MOI) in the presence or absence of DEVD-CHO (100 μM). n = 3. (g) Activation of caspase-3 was determined by immunoblot analyses with anti-cleaved caspase-3 Ab. n = 3.