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The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice

O F Bueno1, L J De Windt, K M Tymitz

  • 1Department of Pediatrics, University of Cincinnati, Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.

The EMBO Journal
|December 2, 2000
PubMed

Insights

Activating the MEK1-ERK1/2 pathway in mice stimulates physiologic cardiac hypertrophy, enhancing heart function and providing resistance to apoptosis. This study clarifies the in vivo role of specific mitogen-activated protein kinase (MAPK) pathways in the heart.

Area of Science:

  • Cardiovascular biology
  • Molecular signaling
  • Physiology

Background:

  • Mitogen-activated protein kinase (MAPK) pathways, including ERK, JNK, and p38, are known regulators of cardiomyocyte hypertrophy in vitro.
  • The specific roles of individual MAPK pathways in vivo cardiac hypertrophy remain incompletely understood.

Purpose of the Study:

  • To investigate the in vivo function of the MEK1-ERK1/2 signaling pathway in cardiac hypertrophy and function.
  • To determine the effects of sustained MEK1 activation on cardiac structure, function, and apoptosis resistance.

Main Methods:

  • Generation of nine transgenic mouse lines with cardiac-restricted expression of activated MEK1 cDNA.
  • Assessment of cardiac hypertrophy, function (echocardiography, working heart preparation), and signaling pathway activation (ERK1/2, p38, JNK).
  • Evaluation of resistance to apoptotic stimuli in MEK1 transgenic mice and MEK1-infected cardiomyocytes.

Main Results:

  • MEK1 transgenic mice developed concentric cardiac hypertrophy without cardiomyopathy or lethality.
  • Significant increases in cardiac function were observed, with no signs of decompensation over time.
  • Activation of ERK1/2, but not p38 or JNK, was confirmed in MEK1 transgenic hearts and cardiomyocytes.
  • MEK1 activation conferred partial resistance to apoptotic stimuli.

Conclusions:

  • The MEK1-ERK1/2 signaling pathway promotes a physiologic cardiac hypertrophy response in vivo.
  • This pathway enhances cardiac function and provides a degree of protection against apoptosis.
  • Findings highlight the specific role of the MEK1-ERK1/2 axis in adaptive cardiac remodeling.

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