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J Thorac Cardiovasc Surg 2001;121:773-781
© 2001 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Inactivation of the MEK/ERK pathway in the myocardium during cardiopulmonary bypass

From the Division of Cardiothoracic Surgery, Department of Surgery,^a Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Mass, and the Department of Cellular Biology,^b University of Brasilia, Brasilia, DF, Brazil.

Supported by grant RO1 HL46716 (F.W.S.) from the National Institutes of Health, National Heart, Lung, and Blood Institute.
E. G. Araujo is supported by a fellowship from Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil. R. Faro is supported by a fellowship from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP), Brazil.

Received for publication June 7, 2000. Revisions requested Aug 22, 2000; revisions received Oct 9, 2000. Accepted for publication Nov 8, 2000. Address for reprints: Frank W. Sellke, MD, Beth Israel Deaconess Medical Center, Division of Cardiothoracic Surgery, 110 Francis St, LMOB suite 2A, Boston MA 02215 (E-mail: fsellke{at}caregroup.harvard.edu).

Abstract

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.

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