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The MEK1–ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice
Author(s) -
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 ChangFu,
Kitsis Richard N.,
Molkentin Jeffery D.
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.23.6341
Subject(s) - biology , transgene , genetically modified mouse , mapk/erk pathway , kinase , signal transduction , protein kinase a , p38 mitogen activated protein kinases , muscle hypertrophy , microbiology and biotechnology , medicine , endocrinology , biochemistry , gene
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 apoptotsis.