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

Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C–deficient mice

“…Although cardiac function in Lmna L530P/L530P mice has not been reported, the differences in heart size between these two mouse models may be explained by relatively greater impairment of LV contraction and/or less compensatory myocardial remodeling in Lmna -/-mice. The consequences of small myocytes in dilated hearts have been evaluated in detail in transgenic mice overexpressing the myelin basic protein kinase, mammalian sterile 20-like kinase 1 (64). Increased LV diameter and wall thinning in these mice were attributed to altered interactions between myocytes and lateral myocyte slippage.…”

Role of apoptosis in ventricular remodeling

“…Activating caspases, whether through overexpression of caspase activators, such as mammalian sterile 2-like kinase 1, which is a substrate and activator of caspase 3 [29], or cardiac-specific caspase 3 itself [30], results in severe cardiomyopathy through apoptotic mechanisms. In the same way, ablating apoptosis signal-regulating kinase, which plays an important role in regulating left ventricular (LV) remodeling by promoting apoptosis [31] or caspase 1 [32] (which is not apoptotic by itself but is related to activation of other intermediates), attenuates apoptosis and ventricular remodeling.…”

A matter of life and death: cardiac myocyte apoptosis and regeneration

“…The elegance of the two transgenic mouse models of dilated cardiomyopathy published here (4,5) is that the cardiac pathology depends strictly on myocyte death as clearly demonstrated by rescue of the phenotype by inhibition of caspase activation. Apoptotic cell death in these animals produces changes in heart size and shape that are consistent with an architectural rearrangement of myocytes, involving sideto-side slippage of cells within the wall (18).…”

“…In this new light, the presence, regulation, and physiological consequences of myocyte apoptosis have gained new significance. Two papers in this issue of the JCI highlight the effect of this type of myocyte death in cardiac performance and provide new insights on the role of myocyte death and renewal in cardiovascular physiology (4,5).…”