期刊
EMBO JOURNAL
卷 20, 期 11, 页码 2757-2767出版社
OXFORD UNIV PRESS
DOI: 10.1093/emboj/20.11.2757
关键词
dilated cardiomyopathy; heart; leukemia inhibitory factor; mitogen-activated protein kinase
资金
- NIDDK NIH HHS [R01 DK034128, DK34128, R37 DK034128] Funding Source: Medline
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 MEKS-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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