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Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy.

Authors: Nicol, RL  Frey, N  Pearson, G  Cobb, M  Richardson, J  Olson, EN 
Citation: Nicol RL, etal., EMBO J. 2001 Jun 1;20(11):2757-67.
Pubmed: (View Article at PubMed) PMID:11387209
DOI: Full-text: DOI:10.1093/emboj/20.11.2757

Mitogen-activated protein kinase (MAPK) pathways couple intrinsic and extrinsic signals to hypertrophic growth of cardiomyocytes. The MAPK kinase MEK5 activates the MAPK ERK5. To investigate the potential involvement of MEK5-ERK5 in cardiac hypertrophy, we expressed constitutively active and dominant-negative forms of MEK5 in cardiomyocytes in vitro. MEK5 induced a form of hypertrophy in which cardiomyocytes acquired an elongated morphology and sarcomeres were assembled in a serial manner. The cytokine leukemia inhibitory factor (LIF), which stimulates MEK5 activity, evoked a similar response. Moreover, a dominant-negative MEK5 mutant specifically blocked LIF-induced elongation of cardiomyocytes and reduced expression of fetal cardiac genes without blocking other aspects of LIF-induced hypertrophy. Consistent with the ability of MEK5 to induce serial assembly of sarcomeres in vitro, cardiac-specific expression of activated MEK5 in transgenic mice resulted in eccentric cardiac hypertrophy that progressed to dilated cardiomyopathy and sudden death. These findings reveal a specific role for MEK5-ERK5 in the induction of eccentric cardiac hypertrophy and in transduction of cytokine signals that regulate serial sarcomere assembly.

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CRRD Object Information
CRRD ID: 1580866
Created: 2006-08-30
Species: All species
Last Modified: 2006-08-30
Status: ACTIVE



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