on August 2, 2004
Published online before print August 2, 2004, doi: 10.1161/01.CIR.0000138190.50127.6A
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Submitted on September 15, 2003
From the Center for Cardiovascular Research, Department of Internal Medicine (I.S.H., S.Z., I.T., A.K., C.W., A.J.M.), and Department of Cell Biology and Physiology (A.J.M.), Washington University School of Medicine, St Louis, Mo. * To whom correspondence should be addressed. E-mail: amuslin{at}im.wustl.edu.
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.
Revised on May 6, 2004
Accepted on May 11, 2004
Raf-1 Kinase Is Required for Cardiac Hypertrophy and Cardiomyocyte Survival in Response to Pressure Overload
Ian S. Harris MD,
Key words: proto-oncogene proteins c-raf • protein kinases • cardiomegaly • signal transduction
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