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Inactivation of the MEK/ERK pathway in the myocardium during cardiopulmonary bypass
E G Araujo1, C Bianchi, K Sato
1Division of Cardiothoracic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA 02215, USA.
Objectives:
A general pro-inflammatory response after cardiopulmonary bypass (CPB) may involve changes in signal transduction and in part be responsible for arrhythmias and myocardial dysfunction after cardiac surgery. The MEK/ERK (mitogen-activated protein kinase kinase/extracellular regulated kinase) pathway is common to many stimuli and may play a pivotal role in morbidity 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 minutes of normothermic CPB and after 90 minutes of post-CPB perfusion. The activities and protein levels of kinases MEK1/2, ERK1/2, a cellular tyrosine kinase (c-Src), protein kinase B (Akt), and the protein levels of mitogen-activated protein kinase phosphatase (MKP-1) were studied by immunoblotting ventricular and atrial myocardium lysates and labeling sections with antibodies 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 ventricular and atrial myocardium with an increase in MKP-1, a negative regulator of ERK1/2. 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 controls. The decrease of ERK1/2 and MEK1/2 phosphorylation 90 minutes after termination 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 mechanisms in the MEK/ERK signal transduction machinery in myocardium subjected to CPB.
Insights
Cardiopulmonary bypass (CPB) inactivates the MEK/ERK signaling pathway in pig hearts, indicated by increased MKP-1. This suggests inhibitory mechanisms dominate the heart
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Signal Transduction
Background:
- Cardiopulmonary bypass (CPB) can induce a pro-inflammatory response, potentially causing arrhythmias and myocardial dysfunction.
- The MEK/ERK (mitogen-activated protein kinase kinase/extracellular regulated kinase) pathway is implicated in cellular responses to various stimuli and may play a role in CPB-related morbidity.
Purpose of the Study:
- To investigate alterations in the MEK/ERK signaling pathway and associated enzymes within the myocardium following CPB.
- To determine if CPB specifically impacts the MEK/ERK pathway compared to other signaling cascades.
Main Methods:
- Ventricular and atrial tissues from pigs were analyzed before and after 90 minutes of normothermic CPB.
- Kinase activities and protein levels (MEK1/2, ERK1/2, c-Src, Akt, MKP-1) were assessed using immunoblotting and immunohistochemistry.
- Control pigs underwent sham procedures without CPB.
Main Results:
- A consistent inactivation of the MEK/ERK pathway was observed in both ventricular and atrial myocardium post-CPB.
- An increase in mitogen-activated protein kinase phosphatase-1 (MKP-1), a negative regulator of ERK1/2, was detected.
- Activities of c-Src and Akt remained unchanged, indicating pathway specificity.
- Confocal microscopy confirmed decreased ERK1/2 and MEK1/2 phosphorylation and increased nuclear MKP-1 levels after CPB.
Conclusions:
- CPB induces inhibitory mechanisms within the MEK/ERK signal transduction pathway in the myocardium.
- These findings highlight specific molecular events occurring in the heart during and after CPB, potentially contributing to post-operative complications.
