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 Molina, Atsuko Yatani, Dorothy E. Vatner, Stephen F. Vatner, Junichi Sadoshima

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165 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1463-1474
Number of pages12
JournalJournal of Clinical Investigation
Volume111
Issue number10
DOIs
StatePublished - 1 Jan 2003

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Dilated Cardiomyopathy
Cardiac Myocytes
Muscle Cells
Hypertrophy
Apoptosis
Transgenic Mice
Phosphotransferases
Starlings
Myelin Basic Protein
Cardiomegaly
Caspases
Cardiomyopathies
Cardiac Output
Protein Kinases
Reperfusion
Cell Death
Ischemia

Cite this

Yamamoto, Shimako ; Yang, Guiping ; Zablocki, Daniela ; Liu, Jing ; Hong, Chull ; Kim, Song Jung ; Soler, Sandra ; Odashima, Mari ; Thaisz, Jill ; Yehia, Ghassan ; Molina, Carlos ; Yatani, Atsuko ; Vatner, Dorothy E. ; Vatner, Stephen F. ; Sadoshima, Junichi. / Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 10. pp. 1463-1474.
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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.",
author = "Shimako Yamamoto and Guiping Yang and Daniela Zablocki and Jing Liu and Chull Hong and Kim, {Song Jung} and Sandra Soler and Mari Odashima and Jill Thaisz and Ghassan Yehia and Carlos Molina and Atsuko Yatani and Vatner, {Dorothy E.} and Vatner, {Stephen F.} and Junichi Sadoshima",
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Yamamoto, S, Yang, G, Zablocki, D, Liu, J, Hong, C, Kim, SJ, Soler, S, Odashima, M, Thaisz, J, Yehia, G, Molina, C, Yatani, A, Vatner, DE, Vatner, SF & Sadoshima, J 2003, 'Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy', Journal of Clinical Investigation, vol. 111, no. 10, pp. 1463-1474. https://doi.org/10.1172/JCI17459

Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy. / Yamamoto, Shimako; Yang, Guiping; Zablocki, Daniela; Liu, Jing; Hong, Chull; Kim, Song Jung; Soler, Sandra; Odashima, Mari; Thaisz, Jill; Yehia, Ghassan; Molina, Carlos; Yatani, Atsuko; Vatner, Dorothy E.; Vatner, Stephen F.; Sadoshima, Junichi.

In: Journal of Clinical Investigation, Vol. 111, No. 10, 01.01.2003, p. 1463-1474.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy

AU - Yamamoto, Shimako

AU - Yang, Guiping

AU - Zablocki, Daniela

AU - Liu, Jing

AU - Hong, Chull

AU - Kim, Song Jung

AU - Soler, Sandra

AU - Odashima, Mari

AU - Thaisz, Jill

AU - Yehia, Ghassan

AU - Molina, Carlos

AU - Yatani, Atsuko

AU - Vatner, Dorothy E.

AU - Vatner, Stephen F.

AU - Sadoshima, Junichi

PY - 2003/1/1

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N2 - 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.

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U2 - 10.1172/JCI17459

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JF - The Journal of clinical investigation

SN - 0021-9738

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