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.


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.
Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St Louis, Mo, USA.
Ian S
IS
Harris
Shaosong
S
Zhang
Ilya
I
Treskov
Attila
A
Kovacs
Carla
C
Weinheimer
Anthony J
AJ
Muslin
D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications; D006332:Cardiomegaly / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D002470:Cell Survival; D004195:Disease Models, Animal; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000473:pathology*; D011312:Pressure / Q000009:adverse effects; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D019908:Proto-Oncogene Proteins c-raf; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases