Targeted deletion of the extracellular signal-regulated protein kinase 5 attenuates hypertrophic response and promotes pressure overload-induced apoptosis in the heart.
BACKGROUND
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.


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.
Kimura
Tomomi E
TE
Faculty of Life Sciences, University of Manchester, CTF Building, 46 Grafton St, Manchester M13 9NT, United Kingdom.
Jin
Jiawei
J
Zi
Min
M
Prehar
Sukhpal
S
Liu
Wei
W
Oceandy
Delvac
D
Abe
Jun-ichi
J
Neyses
Ludwig
L
Weston
Arthur H
AH
Cartwright
Elizabeth J
EJ
Wang
Xin
X
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002478:Cells, Cultured; D005355:Fibrosis; D006973:Hypertension / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D020257:Ventricular Remodeling / Q000187:drug effects
D000814:Aniline Compounds; C533207:BIX 02189; D007211:Indoles; D018006:Myogenic Regulatory Factors; D047428:Protein Kinase Inhibitors; D048054:Mitogen-Activated Protein Kinase 7