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Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte
Shimako Yamamoto1, Guiping Yang, Daniela Zablocki
1Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, and Department of Gynecology, Obstetrics and Women's Health, University of Medicine & Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
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.
Insights
Mammalian sterile 20-like kinase 1 (Mst1) initiates cardiac myocyte apoptosis and inhibits hypertrophy. Mst1 activation in heart cells leads to dilated cardiomyopathy by disrupting the heart
Area of Science:
- Cardiovascular Biology
- Cell Death Pathways
- Molecular Cardiology
Background:
- Mammalian sterile 20-like kinase 1 (Mst1) activation by genotoxic compounds induces apoptosis in certain cell types.
- The role of Mst1 in pathological cardiac cell death remains unclear.
Purpose of the Study:
- To investigate the role of Mst1 in cardiac myocyte apoptosis and hypertrophy.
- To determine Mst1's involvement in pathological cardiac conditions like ischemia/reperfusion.
Main Methods:
- Investigated Mst1 activation by proapoptotic stimuli in cardiac myocytes.
- Utilized cardiac-specific Mst1 overexpression in transgenic mice.
- Examined Mst1 activation during in vivo ischemia/reperfusion.
- Assessed the impact of dominant-negative Mst1 on pathological insults.
Main Results:
- Mst1 is a key myelin basic protein kinase activated by proapoptotic stimuli in cardiac myocytes.
- Mst1 overexpression in mice caused caspase activation, apoptosis, and dilated cardiomyopathy.
- Mst1 inhibited compensatory myocyte hypertrophy, impairing the Frank-Starling mechanism.
- Mst1 activation was observed in the mouse heart following ischemia/reperfusion.
- Suppression of Mst1 protected cardiac myocytes from pathological insults.
Conclusions:
- Mst1 acts as a critical initiator of apoptosis and an inhibitor of hypertrophy in cardiac myocytes.
- Mst1 plays a significant role in the development of a novel form of cardiomyopathy.
- Mst1 is implicated in cardiac dysfunction following ischemia/reperfusion injury.
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