Published online before print August 2, 2004, doi: 10.1161/01.CIR.0000138190.50127.6A
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(Circulation. 2004;110:718-723.)
© 2004 American Heart Association, Inc.
Original Articles |
Raf-1 Kinase Is Required for Cardiac Hypertrophy and Cardiomyocyte Survival in Response to Pressure Overload
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.
Correspondence to Anthony J. Muslin, MD, Box 8086, 660 S Euclid Ave, St Louis, MO 63110. E-mail amuslin{at}im.wustl.edu
Received September 15, 2003; de novo received January 28, 2004; revision received May 6, 2004; accepted May 11, 2004.
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.
Key Words: proto-oncogene proteins c-raf • protein kinases • cardiomegaly • signal transduction
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