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

Orlando F. Bueno, Leon J. De Windt, Kevin M. Tymitz, Sandra A. Witt, Thomas R. Kimball, Raisa Klevitsky, Timothy E. Hewett, Steven P. Jones, David J. Lefer, Chang Fu Peng, Richard N. Kitsis, Jeffery D. Molkentin

Research output: Contribution to journalArticle

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Abstract

Members of the mitogen-activated protein kinase (MAPK) cascade such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 are implicated as important regulators of cardiomyocyte hypertrophic growth in culture. However, the role that individual MAPK pathways play in vivo has not been extensively evaluated. Here we generated nine transgenic mouse lines with cardiac-restricted expression of an activated MEK1 cDNA in the heart. MEK1 transgenic mice demonstrated concentric hypertrophy without signs of cardiomyopathy or lethality up to 12 months of age. MEK1 transgenic mice showed a dramatic increase in cardiac function, as measured By echocardiography and isolated working heart preparation, without signs of decompensation over time. MEK1 transgenic mice and MEK1 adenovirus-infected neonatal cardiomyocytes each demonstrated ERK1/2, but not p38 or JNK, activation. MEK1 transgenic mice and MEK1 adenovirus-infected cultured cardiomyocytes were also partially resistant to apoptotic stimuli. The results of the present study indicate that the MEK1-ERK1/2 signaling pathway stimulates a physiologic hypertrophy response associated with augmented cardiac function and partial resistance to apoptosis.

Original languageEnglish (US)
Pages (from-to)6341-6350
Number of pages10
JournalEMBO Journal
Volume19
Issue number23
StatePublished - Dec 1 2000

Fingerprint

MAP Kinase Signaling System
JNK Mitogen-Activated Protein Kinases
Cardiomegaly
Mitogen-Activated Protein Kinases
Transgenic Mice
Echocardiography
Cardiac Myocytes
Extracellular Signal-Regulated MAP Kinases
Adenoviridae
Complementary DNA
Chemical activation
Hypertrophy
Apoptosis
Cardiomyopathies
Growth
Isolated Heart Preparation

Keywords

  • Cardiac
  • Cardiomyopathy
  • Hypertrophy
  • MAPK
  • Transgenic

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Bueno, O. F., De Windt, L. J., Tymitz, K. M., Witt, S. A., Kimball, T. R., Klevitsky, R., ... Molkentin, J. D. (2000). The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO Journal, 19(23), 6341-6350.

The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. / Bueno, Orlando F.; De Windt, Leon J.; Tymitz, Kevin M.; Witt, Sandra A.; Kimball, Thomas R.; Klevitsky, Raisa; Hewett, Timothy E.; Jones, Steven P.; Lefer, David J.; Peng, Chang Fu; Kitsis, Richard N.; Molkentin, Jeffery D.

In: EMBO Journal, Vol. 19, No. 23, 01.12.2000, p. 6341-6350.

Research output: Contribution to journalArticle

Bueno, OF, De Windt, LJ, Tymitz, KM, Witt, SA, Kimball, TR, Klevitsky, R, Hewett, TE, Jones, SP, Lefer, DJ, Peng, CF, Kitsis, RN & Molkentin, JD 2000, 'The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice', EMBO Journal, vol. 19, no. 23, pp. 6341-6350.
Bueno OF, De Windt LJ, Tymitz KM, Witt SA, Kimball TR, Klevitsky R et al. The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO Journal. 2000 Dec 1;19(23):6341-6350.
Bueno, Orlando F. ; De Windt, Leon J. ; Tymitz, Kevin M. ; Witt, Sandra A. ; Kimball, Thomas R. ; Klevitsky, Raisa ; Hewett, Timothy E. ; Jones, Steven P. ; Lefer, David J. ; Peng, Chang Fu ; Kitsis, Richard N. ; Molkentin, Jeffery D. / The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. In: EMBO Journal. 2000 ; Vol. 19, No. 23. pp. 6341-6350.
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