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.
Harris
Ian S
IS
Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St Louis, Mo, USA.
Zhang
Shaosong
S
Treskov
Ilya
I
Kovacs
Attila
A
Weinheimer
Carla
C
Muslin
Anthony J
AJ
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