Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload
Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload
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DOI：
10.1161/01.cir.0000138190.50127.6a
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发表时间：
2004-08-10
期刊：
影响因子：
37.8
通讯作者：
Muslin, AJ
中科院分区：
文献类型：
--
作者：
Harris, IS;Zhang, SS;Muslin, AJ
背景-心脏肥厚是对压力超负荷的常见反应，并与死亡率增加有关。心脏中的机械应激导致小GTP酶ras和Raf-1/MEK/ERK信号级联激活以及其他信号通路。方法和结果-为了确定心肌肥厚发病机制中对丝氨酸/苏氨酸激酶Raf-1的需求，我们建立了心脏特异表达显性阴性形式Raf-1(dN-Raf)的转基因小鼠。在没有刺激性刺激的情况下，DN-Raf小鼠出生时看起来正常，具有生育能力，心脏结构和功能正常。压力超负荷时，心肌细胞外信号调节激酶(ERK)活性被抑制，而c-jun氨基末端激酶(JNK)和p38丝裂原活化蛋白激酶(MAPK)活性正常。Dn-Raf小鼠对压力超负荷和心肌细胞凋亡的发展敏感，35%的动物在主动脉缩窄后7天内死亡。存活的DN-Raf动物对横断主动脉缩窄所致的心肌肥厚和肥大基因的诱导具有明显的抵抗作用。结论--这些结果表明Raf-1的活性对于心肌肥厚和压力超负荷所致的心肌细胞存活是必不可少的。
Background-Cardiac hypertrophy is a common response to pressure overload and is associated with increased mortality. Mechanical stress in the heart results in the activation of the small GTPase ras and the Raf-1/MEK/ERK signaling cascade in addition to other signaling pathways.Methods and Results-In an attempt to determine the requirement for the serine/threonine kinase Raf-1 in the pathogenesis of cardiac hypertrophy, we generated transgenic mice with cardiac-specific expression of a dominant negative form of Raf-1 (DN-Raf). DN-Raf mice appeared normal at birth, were fertile, and had normal cardiac structure and function in the absence of provocative stimulation. In response to pressure overload, cardiac extracellular signal-regulated kinase (ERK) activation was inhibited, but c-Jun N-terminal kinase (JNK) activation and p38 mitogen-activated protein kinase (MAPK) activation were normal. DN-Raf mice were sensitized to pressure overload and the development of cardiomyocyte apoptosis, and >35% of animals died within 7 days of aortic banding. Surviving DN-Raf animals were markedly resistant to the development of cardiac hypertrophy and hypertrophic gene induction in response to transverse aortic constriction.Conclusions-These results establish that Raf-1 kinase activity is essential for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload.