MEF2 is upregulated during cardiac hypertrophy and is required for normal post-natal growth of the myocardium.
In mammals, growth of the fetal heart is regulated by proliferation of cardiac muscle cells. At later stages of pre-natal life, this proliferation diminishes profoundly [1] [2] and the dramatic expansion in heart size during the transition to adulthood is due exclusively to hypertrophy of individual cardiomyocytes [3] [4] [5]. Cardiomyocyte hypertrophy also contributes to the pathology of most post-natal heart disease [6] [7] [8] [9] [10]. Within this context, numerous signal transduction pathways have been implicated as the link between the effector(s) and altered cardiac gene expression [11] [12] [13] [14] [15] [16]. A common pathway has yet to be discovered, however. Here, we found that the activity of the stress-activated kinase p38 was enhanced in both types of cardiomyocyte hypertrophy. We also found that a target of the activated p38 kinase is the cardiac transcription factor MEF2. Transgenic mice expressing a dominant-negative form of MEF2C displayed attenuated post-natal growth of the myocardium. These results provide the first evidence for a single pathway regulating both normal and pathologic cardiomyocyte hypertrophy.
Kolodziejczyk
S M
SM
Ottawa Hospital Research Institute, Ottawa Hospital General Campus, Centre for Molecular Medicine, Ottawa, Ontario, Canada K1H 8L6.
Wang
L
L
Balazsi
K
K
DeRepentigny
Y
Y
Kothary
R
R
Megeney
L A
LA
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006321:Heart / Q000254:growth & development*; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases