RATIONALE: Mitogen-activated protein kinase (MAPK) pathways provide a critical 
connection between extrinsic and intrinsic signals to cardiac hypertrophy. 
Extracellular signal-regulated protein kinase (ERK)5, an atypical MAPK is 
activated in the heart by pressure overload. However, the role of ERK5 plays in 
regulating hypertrophic growth and hypertrophy-induced apoptosis is not 
completely understood.
OBJECTIVE: Herein, we investigate the in vivo role and signaling mechanism 
whereby ERK5 regulates cardiac hypertrophy and hypertrophy-induced apoptosis.
METHODS AND RESULTS: We generated and examined the phenotypes of mice with 
cardiomyocyte-specific deletion of the erk5 gene (ERK5(cko)). In response to 
hypertrophic stress, ERK5(cko) mice developed less hypertrophic growth and 
fibrosis than controls. However, increased apoptosis together with upregulated 
expression levels of p53 and Bad were observed in the mutant hearts. 
Consistently, we found that silencing ERK5 expression or specific inhibition of 
its kinase activity using BIX02189 in neonatal rat cardiomyocytes (NRCMs) 
reduced myocyte enhancer factor (MEF)2 transcriptional activity and blunted 
hypertrophic responses. Furthermore, the inhibition of MEF2 activity in NRCMs 
using a non-DNA binding mutant form of MEF2 was found to attenuate the 
ERK5-regulated hypertrophic response.
CONCLUSIONS: These results reveal an important function of ERK5 in cardiac 
hypertrophic remodeling and cardiomyocyte survival. The role of ERK5 in 
hypertrophic remodeling is likely to be mediated via the regulation of MEF2 
activity.