TY - JOUR
T1 - Activation of MTK1/MEKK4 induces cardiomyocyte death and heart failure
AU - Mizote, Isamu
AU - Yamaguchi, Osamu
AU - Hikoso, Shungo
AU - Takeda, Toshihiro
AU - Taneike, Manabu
AU - Oka, Takafumi
AU - Tamai, Takahito
AU - Oyabu, Jota
AU - Matsumura, Yasushi
AU - Nishida, Kazuhiko
AU - Komuro, Issei
AU - Hori, Masatsugu
AU - Otsu, Kinya
PY - 2010/2
Y1 - 2010/2
N2 - MTK1 (MEKK4) is a mitogen-activated protein kinase kinase kinase that regulates the activity of its downstream mitogen-activated kinases, p38, and c-Jun N-terminal kinase (JNK). However, the physiological function of MTK1 in the heart remains to be determined. Here, we attempted to elucidate the function of MTK1 in the heart using in vitro and in vivo models. MTK1 was activated in the hearts of mice subjected to pressure overload-induced heart failure. Overexpression of a constitutively active mutant of MTK1 (MTK1 Delta N) induced apoptosis in isolated neonatal rat cardiomyocytes, whereas a kinase domain-deleted form of MTK1 attenuated H2O2-induced apoptosis. Specific inhibitors of p38 or JNK effectively protected cardiomyocytes from MTK1 Delta N-induced cell death. In mice, cardiac-specific overexpression of MTK1 Delta N resulted in early mortality compared with the lifespan of littermate controls. Echocardiographic analysis revealed increases in end-diastolic and end-systolic left ventricular internal dimensions and a decrease in fractional shortening in MTK1 Delta N transgenic mice. In addition, the mice showed characteristic phenotypes of heart failure such as an increase in lung weight. The number of TUNEL-positive myocytes and the level of cleaved caspase 3 protein were both increased in MTK1 Delta N transgenic mice. Thus, MTK1 plays an important role in the regulation of cell death and is also involved in the pathogenesis of heart failure. (C) 2009 Elsevier Ltd. All rights reserved.
AB - MTK1 (MEKK4) is a mitogen-activated protein kinase kinase kinase that regulates the activity of its downstream mitogen-activated kinases, p38, and c-Jun N-terminal kinase (JNK). However, the physiological function of MTK1 in the heart remains to be determined. Here, we attempted to elucidate the function of MTK1 in the heart using in vitro and in vivo models. MTK1 was activated in the hearts of mice subjected to pressure overload-induced heart failure. Overexpression of a constitutively active mutant of MTK1 (MTK1 Delta N) induced apoptosis in isolated neonatal rat cardiomyocytes, whereas a kinase domain-deleted form of MTK1 attenuated H2O2-induced apoptosis. Specific inhibitors of p38 or JNK effectively protected cardiomyocytes from MTK1 Delta N-induced cell death. In mice, cardiac-specific overexpression of MTK1 Delta N resulted in early mortality compared with the lifespan of littermate controls. Echocardiographic analysis revealed increases in end-diastolic and end-systolic left ventricular internal dimensions and a decrease in fractional shortening in MTK1 Delta N transgenic mice. In addition, the mice showed characteristic phenotypes of heart failure such as an increase in lung weight. The number of TUNEL-positive myocytes and the level of cleaved caspase 3 protein were both increased in MTK1 Delta N transgenic mice. Thus, MTK1 plays an important role in the regulation of cell death and is also involved in the pathogenesis of heart failure. (C) 2009 Elsevier Ltd. All rights reserved.
U2 - 10.1016/j.yjmcc.2009.10.010
DO - 10.1016/j.yjmcc.2009.10.010
M3 - Article
C2 - 19850048
SN - 0022-2828
VL - 48
SP - 302
EP - 309
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 2
ER -