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

Osamu 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. Chien, Atsushi Matsuzawa, Chiharu Sadamitsu, Hidenori Ichijo, Manuela Baccarini, Masatsugu HoriKinya Otsu

Research output: Contribution to journalArticlepeer-review

166 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)937-943
Number of pages7
JournalJournal of Clinical Investigation
Issue number7
Publication statusPublished - 2004 Oct
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)


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