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PMID: 11101507 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The EMBO journal ·Vol. 19 ·No. 23 ·2000-12-01 ·Pages 6341-50

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

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 apoptotsis.

MeSH Terms
Actinin/metabolism Adenoviridae/metabolism Age Factors Animals Animals, Newborn Apoptosis Body Weight Cardiomegaly/metabolism Caspase 3 Caspases/metabolism Cells, Cultured DNA Fragmentation DNA, Complementary/metabolism Echocardiography Electrophoresis, Polyacrylamide Gel Immunohistochemistry In Situ Nick-End Labeling Leucine/metabolism MAP Kinase Kinase 1 MAP Kinase Signaling System Mice Mice, Transgenic Mitogen-Activated Protein Kinase 1/metabolism Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinase 8 Mitogen-Activated Protein Kinase Kinases/metabolism Mitogen-Activated Protein Kinases/metabolism Myocardium/metabolism Organ Size Plasmids/metabolism Protein Serine-Threonine Kinases/metabolism RNA/metabolism Rats Reperfusion Injury Reverse Transcriptase Polymerase Chain Reaction Signal Transduction
Chemicals
DNA, Complementary Actinin RNA Protein Serine-Threonine Kinases Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinase 8 Mitogen-Activated Protein Kinases MAP Kinase Kinase 1 Map2k1 protein, mouse Mitogen-Activated Protein Kinase Kinases Casp3 protein, mouse Casp3 protein, rat Caspase 3 Caspases Leucine
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Bueno O F
Department of Pediatrics, University of Cincinnati, Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
De Windt L J
Tymitz K M
Witt S A
Kimball T R
Klevitsky R
Hewett T E
Jones S P
Lefer D J
Peng C F
Kitsis R N
Molkentin J D
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/19.23.6341
Published
2000-12-01
Pages
6341-50
Language
English
Region
England
NLM ID
8208664
PMCID
PMC305855
Subset
IM
Grants
NHLBI NIH HHS · HL52318 · United States
NHLBI NIH HHS · P50 HL052318 · United States
NHLBI NIH HHS · R01 HL062927 · United States
NHLBI NIH HHS · T32 HL007752 · United States
NHLBI NIH HHS · HL69562 · United States
NHLBI NIH HHS · HL62927 · United States
External Links
PubMed source DOI: 10.1093/emboj/19.23.6341 PMC Full Text View journal details
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