Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis.
The Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathway regulates diverse cellular processes such as proliferation, differentiation, and apoptosis and is implicated as an important contributor to the pathogenesis of cardiac hypertrophy and heart failure. To examine the in vivo role of Raf-1 in the heart, we generated cardiac muscle-specific Raf-1-knockout (Raf CKO) mice with Cre-loxP-mediated recombination. The mice demonstrated left ventricular systolic dysfunction and heart dilatation without cardiac hypertrophy or lethality. The Raf CKO mice showed a significant increase in the number of apoptotic cardiomyocytes. The expression level and activation of MEK1/2 or ERK showed no difference, but the kinase activity of apoptosis signal-regulating kinase 1 (ASK1), JNK, or p38 increased significantly compared with that in controls. The ablation of ASK1 rescued heart dysfunction and dilatation as well as cardiac fibrosis. These results indicate that Raf-1 promotes cardiomyocyte survival through a MEK/ERK-independent mechanism.
Yamaguchi
Osamu
O
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Watanabe
Tetsuya
T
Nishida
Kazuhiko
K
Kashiwase
Kazunori
K
Higuchi
Yoshiharu
Y
Takeda
Toshihiro
T
Hikoso
Shungo
S
Hirotani
Shinichi
S
Asahi
Michio
M
Taniike
Masayuki
M
Nakai
Atsuko
A
Tsujimoto
Ikuko
I
Matsumura
Yasushi
Y
Miyazaki
Jun-ichi
J
Chien
Kenneth R
KR
Matsuzawa
Atsushi
A
Sadamitsu
Chiharu
C
Ichijo
Hidenori
H
Baccarini
Manuela
M
Hori
Masatsugu
M
Otsu
Kinya
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004789:Enzyme Activation; D006321:Heart / Q000503:physiopathology*; D006439:Hemodynamics; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*
D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5