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- Title
Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis.
- Authors
Yamaguchi, Osamu; Watanabe, Tetsuya; Nishida, Kazuhiko; Kashiwase, Kazunori; Higuchi, Yoshiharu; Takeda, Toshihiro; Hikoso, Shungo; Hirotani, Shinichi; Asahi, Michio; Taniike, Masayuki; Nakai, Atsuko; Tsujimoto, Ikuko; Matsumura, Yasushi; Miyazaki, Jun-Ichi; Chien, Kenneth R.; Matsuzawa, Atsushi; Sadamitsu, Chiharu; Ichijo, Hidenori; Baccarini, Manuela; Hon, Masatsugu
- Abstract
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 (RafCKO) 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.
- Subjects
HEART diseases; APOPTOSIS; HEART cells; GENES; HEART failure; CELL death
- Publication
Journal of Clinical Investigation, 2004, Vol 114, Issue 7, p937
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI200420317