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 degrees 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. Beta-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 beta-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 beta-adrenergic receptor signaling.
Conclusions: Current techniques of myocardial preservation are associated with inhibition of protein kinase C alpha activity and maintenance of intact beta-adrenergic receptor signaling. Activation of protein kinase C alpha leads to enhanced beta-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.