Circulation Research. 2002;91:776-781
doi: 10.1161/01.RES.0000038488.38975.1A
doi: 10.1161/01.RES.0000038488.38975.1A
© 2002 American Heart Association, Inc.
Reviews |
Involvement of Extracellular Signal-Regulated Kinases 1/2 in Cardiac Hypertrophy and Cell Death
From the Department of Pediatrics, University of Cincinnati, Division of Molecular Cardiovascular Biology, Children’s Hospital Medical Center, Cincinnati, Ohio.
Correspondence to Jeffery D. Molkentin, PhD, University of Cincinnati, Dept of Pediatrics, Division of Molecular, Cardiovascular Biology, Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail jeff.molkentin{at}chmcc.org
In response to pathophysiological stress, the adult heart undergoes hypertrophic enlargement characterized by an increase in the cross-sectional area of individual myofibers. Although cardiac hypertrophy is initially a compensatory response, sustained hypertrophy is a leading predictor for the development of heart failure. At the molecular level, disease-related stimuli invoke endocrine, paracrine, and autocrine regulatory circuits, which directly influence cardiomyocyte hypertrophy, in part, through membrane bound G protein–coupled receptors and receptor tyrosine kinases. These membrane receptors activate intermediate signal transduction pathways within the cytoplasm such as mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), and calcineurin, which directly modify transcriptional regulatory factors promoting alterations in cardiac gene expression. This review will weigh an increasing body of literature implicating the intermediate signaling pathway consisting of MEK1 and extracellular signal-regulated kinases (ERK1/2) as important regulators of cardiac hypertrophy and myocyte survival. The MEK1-ERK1/2 pathway likely occupies a central regulatory position in the signaling hierarchy of a cardiac myocyte given its unique ability to respond to virtually every characterized hypertrophic agonist and stress stimuli examined to date and based on its ability to promote myocyte growth in vitro and in vivo.
Key Words: heart • hypertrophy • failure • signaling • mitogen-activated protein kinase
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|
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|
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|
|
|
|
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|
|
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|
|
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|
|
|
|
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|
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|
|
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|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 P. Ping A new chapter in cardiac PKC signaling studies: searching for isoform-specific molecular targets. Focus on: "Isoenzyme-selective regulation of SERCA2 gene expression by protein kinase C in neonatal rat ventricular myocytes" Am J Physiol Cell Physiol, July 1, 2003; 285(1): C19 - C21. [Full Text] [PDF]
|
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