Objectives: A general pro-inflammatory response after cardiopulmonary bypas
s (CPB) may involve changes in signal transduction and in part be responsib
le for arrhythmias and myocardial dysfunction after cardiac surgery. The ME
K/ERK (mitogen-activated protein kinase kinase/extracellular regulated kina
se) pathway is common to many stimuli and may play a pivotal role in morbid
ity associated with CPB. We investigated the changes in MEK/ERK pathway and
related enzymes after CPB in pigs.
Methods: We examined ventricular and atrial tissue from pigs before 90 minu
tes of normothermic CPB and after 90 minutes of post-CPB perfusion. The act
ivities and protein levels of kinases MEK1/2, ERK1/2, a cellular tyrosine k
inase (c-Src), protein kinase B (Akt), and the protein levels of mitogen-ac
tivated protein kinase phosphatase (MKP-1) were studied by immunoblotting v
entricular and atrial myocardium lysates and labeling sections with antibod
ies that recognize the activated forms of the kinases and the phosphatase.
Control pigs were subjected to sternotomy and heparinization but not CPB.
Results: We found a consistent inactivation of MEK/ERK pathway in both vent
ricular and atrial myocardium with an increase in MKP-1, a negative regulat
or of ERK 1/2. The activities and protein levels of c-Src and Akt were not
significantly modified before or after CPB, suggesting a certain degree of
specificity for the MEK/ERK pathway. Such changes were not observed in cont
rols. The decrease of ERK1/2 and MEK1/2 phosphorylation 90 minutes after te
rmination of CPB (as well as the increase of nuclear MKP-1 protein levels)
was also apparent by confocal microscopy.
Conclusions: These results collectively reveal a prevalence of inhibitory m
echanisms in the MEK/ERK signal transduction machinery in myocardium subjec
ted to CPB.