Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload

Ian S. Harris, Shaosong Zhang, Ilya Treskov, Attila Kovacs, Carla Weinheimer, Anthony J. Muslin

Research output: Contribution to journalArticlepeer-review

139 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)718-723
Number of pages6
JournalCirculation
Volume110
Issue number6
DOIs
StatePublished - Aug 10 2004

Keywords

  • Cardiomegaly
  • Protein kinases
  • Proto-oncogene proteins c-raf
  • Signal transduction

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