Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis.
Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis.
复制标题
DOI：
10.1172/jci20317
复制
发表时间：
2004-10
期刊：
影响因子：
--
通讯作者：
O. Yamaguchi;Tetsuya Watanabe;K. Nishida;K. Kashiwase;Y. Higuchi;Toshihiro Takeda;S. Hikoso;S. Hirotani;M. Asahi;M. Taniike;Atsuko Nakai;I. Tsujimoto;Y. Matsumura;J. Miyazaki;K. Chien;A. Matsuzawa;C. Sadamitsu;H. Ichijo;M. Baccarini;M. Hori;K. Otsu
中科院分区：
文献类型：
--
作者：
O. Yamaguchi;Tetsuya Watanabe;K. Nishida;K. Kashiwase;Y. Higuchi;Toshihiro Takeda;S. Hikoso;S. Hirotani;M. Asahi;M. Taniike;Atsuko Nakai;I. Tsujimoto;Y. Matsumura;J. Miyazaki;K. Chien;A. Matsuzawa;C. Sadamitsu;H. Ichijo;M. Baccarini;M. Hori;K. Otsu
Raf/MEK/细胞外信号调节激酶（ERK）信号通路调节多种细胞过程，如增殖、分化和凋亡，并且被认为是心脏肥大和心力衰竭的发病机制的重要贡献者。为了研究Raf-1在心脏中的体内作用，我们用Cre-loxP介导的重组产生心肌特异性Raf-1敲除（Raf CKO）小鼠。小鼠表现出左心室收缩功能障碍和心脏扩张，而没有心脏肥大或致死性。Raf CKO小鼠的心肌细胞凋亡数量显著增加。与对照组相比，MEK 1/2和ERK的表达水平和活化没有差异，但凋亡信号调节激酶1（ASK 1）、JNK和p38的激酶活性显著增加。ASK 1的消融挽救了心脏功能障碍和扩张以及心脏纤维化。这些结果表明Raf-1通过MEK/ERK非依赖性机制促进心肌细胞存活。
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.