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.
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Osamu
O
Yamaguchi
Tetsuya
T
Watanabe
Kazuhiko
K
Nishida
Kazunori
K
Kashiwase
Yoshiharu
Y
Higuchi
Toshihiro
T
Takeda
Shungo
S
Hikoso
Shinichi
S
Hirotani
Michio
M
Asahi
Masayuki
M
Taniike
Atsuko
A
Nakai
Ikuko
I
Tsujimoto
Yasushi
Y
Matsumura
Jun-ichi
J
Miyazaki
Kenneth R
KR
Chien
Atsushi
A
Matsuzawa
Chiharu
C
Sadamitsu
Hidenori
H
Ichijo
Manuela
M
Baccarini
Masatsugu
M
Hori
Kinya
K
Otsu
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