Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy

Rebekka L. Nicol, Norbert Frey, Gray Pearson, Melanie Cobb, James Richardson, Eric N. Olson

Research output: Contribution to journalArticlepeer-review

225 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2757-2767
Number of pages11
JournalEMBO Journal
Volume20
Issue number11
DOIs
StatePublished - Jun 1 2001

Keywords

  • Dilated cardiomyopathy
  • Heart
  • Leukemia inhibitory factor
  • Mitogen-activated protein kinase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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