Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload.
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.[1]References
- Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload. Harris, I.S., Zhang, S., Treskov, I., Kovacs, A., Weinheimer, C., Muslin, A.J. Circulation (2004) [Pubmed]
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