Suppression of graft coronary artery disease by a brief treatment with a selective epsilonPKC activator and a deltaPKC inhibitor in murine cardiac allografts.
BACKGROUND
Inhibiting delta protein kinase C (deltaPKC) during reperfusion and activating epsilon PKC (epsilonPKC) 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.


RESULTS
Hearts of FVB mice (H-2q) were transplanted into C57BL/6 mice (H-2b). epsilonPKC activator (psiepsilonRACK) was injected intraperitoneally (20 nmol) into donor mice 20 minutes before procurement. Hearts were then perfused with psiepsilonRACK (1.5 nmol) through the inferior vena cava (IVC) and subsequently submerged in psiepsilonRACK (0.5 micromol/L) for 20 minutes at 4 degrees C. Before reperfusion, the peritoneal cavity of recipients was irrigated with deltaPKC inhibitor (deltaV1-1, 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 epsilonPKC activator and a deltaPKC 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.
Tanaka
Masashi
M
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, CA 94305-5407, USA. masashi@omiya.jichi.ac.jp
Terry
Raya D
RD
Mokhtari
Golnaz K
GK
Inagaki
Koichi
K
Koyanagi
Tomoyoshi
T
Kofidis
Theo
T
Mochly-Rosen
Daria
D
Robbins
Robert C
RC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D003327:Coronary Disease / Q000188:drug therapy* / Q000209:etiology; D016207:Cytokines / Q000096:biosynthesis; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology; D016027:Heart Transplantation; D007249:Inflammation / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy*; D032383:Myocytes, Cardiac / Q000473:pathology; D009336:Necrosis; D009842:Oligopeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D009195:Peroxidase / Q000032:analysis; D011183:Postoperative Complications / Q000188:drug therapy* / Q000209:etiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D007507:Therapeutic Irrigation; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D015815:Cell Adhesion Molecules; D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C477271:His-Asp-Ala-Pro-Ile-Gly-Tyr-Asp; D008562:Membrane Glycoproteins; D009842:Oligopeptides; C477270:Ser-Phe-Asn-Ser-Tyr-Glu-Leu-Gly-Glu-Ser-Leu; D009195:Peroxidase; C497259:Prkcd protein, mouse; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases