Reciprocal modulation of mitogen-activated protein kinases and mitogen-activated protein kinase phosphatase 1 and 2 in failing human myocardium.
BACKGROUND
Mitogen-activated protein kinases (MAPKs), consisting of the ERK1/2, JNKs, and p38-kinase families, play a key role in the regulation of myocyte growth and apoptosis in vitro. The activity of MAPKs is regulated by dual-specificity MAPK phosphatases (MKPs). Because myocardial failure is associated with myocyte hypertrophy and apoptosis, MAPKs may play a pathophysiologic role in human myocardial failure.


RESULTS
We measured MAPKs activities and the protein levels of MAPKs and MKPs (MKP-1 and MKP-2) in the myocardium explanted at the time of transplantation from patients with end-stage failure caused by idiopathic dilated cardiomyopathy (n = 5-7). Nonfailing donor hearts (n = 5-7) were used for comparison. Although the protein levels for JNK1/2 and p38-kinase in failing hearts were not different from levels in nonfailing hearts, the activities of both were decreased (P <.05). Despite a >3-fold increase in the protein level for ERK1/2 in failing hearts, ERK1/2 activity was not increased. Expression of MKP-2 was significantly increased in failing hearts, while expression of MKP-1 was increased in 5 of 7 failing hearts as measured by Western analysis.


CONCLUSIONS
JNK1/2 and p38 activities are decreased in failing human myocardium. Increased expression of MKPs may therefore contribute to decreased MAPKs activity in failing human myocardium.
Communal
Catherine
C
Myocardial Biology Unit, Boston University School of Medicine, Boston, MA, USA.
Colucci
Wilson S
WS
Remondino
Andrea
A
Sawyer
Douglas B
DB
Port
J David
JD
Wichman
Scott E
SE
Bristow
Michael R
MR
Singh
Krishna
K
D000328:Adult; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000201:enzymology*; D002648:Child; D004789:Enzyme Activation; D005260:Female; D006333:Heart Failure / Q000201:enzymology* / Q000209:etiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000032:analysis / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology*; D048051:p38 Mitogen-Activated Protein Kinases
D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases