Activation of MTK1/MEKK4 induces cardiomyocyte death and heart failure.
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 (MTK1DeltaN) induced apoptosis in isolated neonatal rat cardiomyocytes, whereas a kinase domain-deleted form of MTK1 attenuated H(2)O(2)-induced apoptosis. Specific inhibitors of p38 or JNK effectively protected cardiomyocytes from MTK1DeltaN-induced cell death. In mice, cardiac-specific overexpression of MTK1DeltaN 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 MTK1DeltaN 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 MTK1DeltaN transgenic mice. Thus, MTK1 plays an important role in the regulation of cell death and is also involved in the pathogenesis of heart failure.
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Isamu
I
Mizote
Osamu
O
Yamaguchi
Shungo
S
Hikoso
Toshihiro
T
Takeda
Manabu
M
Taneike
Takafumi
T
Oka
Takahito
T
Tamai
Jota
J
Oyabu
Yasushi
Y
Matsumura
Kazuhiko
K
Nishida
Issei
I
Komuro
Masatsugu
M
Hori
Kinya
K
Otsu
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048768:MAP Kinase Kinase Kinase 4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D009928:Organ Specificity / Q000187:drug effects; D051381:Rats; D014463:Ultrasonography
D050505:Mutant Proteins; D006861:Hydrogen Peroxide; D048768:MAP Kinase Kinase Kinase 4