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Activation of MTK1/MEKK4 induces cardiomyocyte death and heart failure

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Isamu Mizote, Osamu Yamaguchi, Shungo Hikoso, Toshihiro Takeda, Manabu Taneike, Takafumi Oka, Takahito Tamai, Jota Oyabu, Yasushi Matsumura, Kazuhiko Nishida, Issei Komuro, Masatsugu Hori, Kinya Otsu

Original languageEnglish
Pages (from-to)302-309
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume48
Issue number2
DOIs
PublishedFeb 2010

King's Authors

Abstract

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.

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