In recent years, much investigation has centered on identifying and characterizing the intracellular signal transduction pathways that control cardiac hypertrophy and heart failure. Numerous intermediate signaling pathways have been implicated as important regulators of cardiac hypertrophy including mitogen-activated protein kinase (MAPK), calcineurin-NFAT, PKC, and many others. However, the role that MAPK signaling plays in mediating cardiac hypertrophy is currently an area of considerable debate. Currently, there is little consensus in the literature as to which of the 3 MAPK signaling branches (ERKs, p38 kinases, or JNKs) are important hypertrophic regulators, and almost nothing has been extended to the heart in vivo. Accordingly, we propose, in vivo, an in depth analysis of the ERK MAPK signaling pathway to characterize its role as a cardiac hypertrophic mediator and its role in cardiac apoptosis. Preliminary studies suggest that the ERK MAPK pathway, but not JNK or p38 MAPK can induce cardiac hypertrophy in vivo and promote protection from apoptotic stimuli. The ERK MAPK signaling pathway induces cardiac hypertrophy, in part, by directly acting on the zinc-finger-containing transcription factor GATA4. Given these data, we propose the hypothesis that an ERK-GATA4 signaling pathway is necessary for mediating cardiac hypertrophy in vitro and in vivo. To test this, the hypertrophic potential of MEK1 dominant negative mice and ERK1/2 knock-out mice will be characterized in vivo. The role that the ERK MAPK pathway plays in mediating cardioprotection (anti-apoptosis) will also be analyzed in response to ischemia/reperfusion. Lastly, the necessity of GATA4 as a downstream hypertrophic transducer of ERK MAPK signaling will be evaluated both in vitro and in vivo. These approaches will suggest the extent to which ERK MAPK and GATA4 are necessary in the development of cardiac hypertrophy in response to pathophysiologic stimuli.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL069779-01
Application #
6606595
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2002-06-06
Project End
2007-04-30
Budget Start
2002-06-06
Budget End
2003-04-30
Support Year
1
Fiscal Year
2002
Total Cost
$305,975
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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