Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis

Autor(en)

Osamu A. Yamaguchi, Tetsuya Watanabe, Kazuhiko Nishida, Kazunori Kashiwase, Yoshiharu Higuchi, Toshihiro Takeda, Shungo Hikoso, Shinichi Hirotani, Michio Asahi, Masayuki Taniike, Atsuko Nakai, Ikuko Tsujimoto, Yasushi Matsumura, Jun Ichi Miyazaki, Kenneth R. R. Chien, Atsushi Matsuzawa, Chiharu Sadamitsu, Hidenori Ichijo, Manuela Baccarini, Masatsugu Hori, Kinya Otsu

Abstrakt

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.

Organisation(en)

Externe Organisation(en)

Osaka University, University of Toronto, Yamanashi University, Harvard University, Japan Science and Technology Agency , University of Tokyo

Journal

Journal of Clinical Investigation

Band

114

Seiten

937-943

Anzahl der Seiten

7

ISSN

0021-9738

Publikationsdatum

2004

Peer-reviewed

Ja

ÖFOS 2012

1060 Biologie

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/cardiacspecific-disruption-of-the-craf1-gene-induces-cardiac-dysfunction-and-apoptosis(6b389dd0-cb09-44a4-ace5-67ecb689b1c3).html