Inhibition of protein kinase Cα improves myocardial β-adrenergic receptor signaling and ventricular function in a model of myocardial preservation

Objective The specific effect of protein kinase Cα, 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 Cα 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 Cα were then studied to specifically examine the effects of protein kinase Cα 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 Cα 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 Cα 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 Cα 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 Cα activity and maintenance of intact β-adrenergic receptor signaling. Activation of protein kinase Cα 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.