Suppression of Graft Coronary Artery Disease by a Brief Treatment With a Selective εPKC Activator and a δPKC Inhibitor in Murine Cardiac Allografts

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Abstract
Background—Inhibiting delta protein kinase C (δPKC) during reperfusion and activating epsilon PKC (εPKC) before ischemia each limits cardiac ischemic injury. Here, we examined whether limiting ischemia-reperfusion injury inhibits graft coronary artery disease (GCAD) and improves murine cardiac allografting.Methods and Results—Hearts of FVB mice (H-2q) were transplanted into C57BL/6 mice (H-2b). εPKC activator (ψεRACK) was injected intraperitoneally (20 nmol) into donor mice 20 minutes before procurement. Hearts were then perfused with ψεRACK (1.5 nmol) through the inferior vena cava (IVC) and subsequently submerged in ψεRACK (0.5 μmol/L) for 20 minutes at 4°C. Before reperfusion, the peritoneal cavity of recipients was irrigated with δPKC inhibitor (δV1-1, 300 nmol); control animals were treated with normal saline. The total ischemic time to the organ was 50 minutes. Two hours after transplantation, production of inflammatory cytokines and adhesion molecules, cardiomyocyte apoptosis, and caspase-3 and caspase-9 (but not caspase-8) activities were significantly reduced in the PKC regulator-treated group. Fas ligand levels (but not Fas) were also significantly reduced in this group. Importantly, GCAD indices, production of inflammatory cytokines, and adhesion molecules were significantly decreased and cardiac allograft function was significantly better as measured up to 30 days after transplantation.ConclusionsAn εPKC activator and a δPKC inhibitor together reduced GCAD. Clinically, these PKC isozyme regulators may be useful for organ preservation and prevention of ischemia-reperfusion injury and graft coronary artery disease in cardiac transplantation.