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J Thorac Cardiovasc Surg 2008;135:172-179
© 2008 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Inhibition of protein kinase C{alpha} improves myocardial β-adrenergic receptor signaling and ventricular function in a model of myocardial preservation

Karen M. D’Souza, PhDa, Natalia N. Petrashevskaya, PhDb, Walter H. Merrill, MDa, Shahab A. Akhter, MDa,*

a Department of Surgery, Section of Cardiothoracic Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio
b Cardiopulmonary Genomics Program, University of Maryland School of Medicine, Baltimore, Md.

Received for publication May 25, 2007; revisions received July 23, 2007; accepted for publication August 15, 2007.

* Address for reprints: Shahab A. Akhter, MD, Assistant Professor of Surgery, Section of Cardiac & Thoracic Surgery, The University of Chicago, 5841 S. Maryland Avenue, MC 5040, Chicago, Ill 60637. (Email: sakhter{at}surgery.bsd.uchicago.edu).

Objective: The specific effect of protein kinase C{alpha}, the primary ventricular calcium-dependent protein kinase C isoform, on myocardial protection is unclear. The objective of this study was to determine the role of protein kinase C{alpha} in myocardial protection and recovery of function after cardioplegic arrest, cold preservation, and normothermic reperfusion, as relevant to cardiac transplantation.

Methods: We used an ex vivo murine model, and hearts were arrested with cold crystalloid cardioplegia or saline as a control and maintained at 4°C for 4 hours. This was followed by normothermic reperfusion for 90 minutes. Transgenic hearts with cardiac-specific activation or inhibition of protein kinase C{alpha} were then studied to specifically examine the effects of protein kinase C{alpha} on myocardial preservation in this model.

Results: Cardioplegic arrest with University of Wisconsin solution led to significantly improved postreperfusion hemodynamics and inhibition of myocardial protein kinase C{alpha} activity relative to that seen in saline-treated control hearts. β-Adrenergic receptor signaling was also preserved with University of Wisconsin solution. Transgenic hearts with enhanced protein kinase C{alpha} activity had poor postreperfusion hemodynamics, impaired β-adrenergic receptor signaling, and increased G protein–coupled receptor kinase 2 activity compared with those seen in nontransgenic control hearts. In contrast, transgenic hearts with inhibited protein kinase C{alpha} activity had even better myocardial protection relative to control hearts and preserved β-adrenergic receptor signaling.

Conclusions: Current techniques of myocardial preservation are associated with inhibition of protein kinase C{alpha} activity and maintenance of intact β-adrenergic receptor signaling. Activation of protein kinase C{alpha} leads to enhanced β-adrenergic receptor desensitization and impaired signaling and ventricular function as a result of increased G protein–coupled receptor kinase 2 activity. This is a novel in vivo mechanism of G protein–coupled receptor kinase 2 activation. Strategies to specifically inhibit these kinases might improve long-term myocardial protection.

Abbreviations and Acronyms ACT = specific activation; ATP = Adenosine triphosphate; βAR = β-Adrenergic receptor; CK = creatine kinase; GRK = G protein–coupled receptor kinase; INH = specific inhibition; PKC = protein kinase C; UW = University of Wisconsin




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