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(Circulation. 2004;110:II-194 – II-199.)
© 2004 American Heart Association, Inc.

Cardiac Transplantation and Surgery for Congestive Heart Failure

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

Masashi Tanaka, MD; Raya D. Terry; Golnaz K. Mokhtari; Koichi Inagaki, MD PhD; Tomoyoshi Koyanagi, PhD; Theo Kofidis, MD; Daria Mochly-Rosen, PhD; Robert C. Robbins, MD

From Department of Cardiothoracic Surgery (M.T., R.D.T., G.K.M., T.K., R.C.R.), Department of Molecular Pharmacology (K.I., T.K., D.M.-R.), Stanford University School of Medicine, Stanford, Calif.

Correspondence to Masashi Tanaka, MD, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, CA 94305-5407. E-mail masashi{at}omiya.jichi.ac.jp

Background— Inhibiting delta protein kinase C (PKC) during reperfusion and activating epsilon PKC (PKC) 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-2^q) were transplanted into C57BL/6 mice (H-2^b). PKC activator (RACK) was injected intraperitoneally (20 nmol) into donor mice 20 minutes before procurement. Hearts were then perfused with RACK (1.5 nmol) through the inferior vena cava (IVC) and subsequently submerged in RACK (0.5 µmol/L) for 20 minutes at 4°C. Before reperfusion, the peritoneal cavity of recipients was irrigated with PKC inhibitor (V1-1, 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.

Conclusions An PKC activator and a PKC 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.

Key Words: reperfusion • apoptosis • transplantation • arteriosclerosis • protein kinase C