Pharmacological inhibition of epsilon PKC suppresses chronic inflammation in murine cardiac transplantation model.
Epsilon protein kinase C (epsilonPKC) plays pivotal roles in myocardial infarction and in heart failure. Although cardiac transplantation is a well-established therapy for severe heart failure, allograft rejection and host inflammatory responses limit graft function and reduce life expectancy. Here we determined whether sustained epsilonPKC inhibition beginning 3 days after transplantation suppress allograft rejection and improve cardiac transplantation using a murine heterotopic transplantation model. Hearts of FVB mice (H-2(q)) were transplanted into C57BL/6 mice (H-2(b)). Delivery of the epsilonPKC inhibitor, TAT(47-57)-epsilonV1-2 (epsilonV1-2, n=9, 20 mg/kg/day), or the carrier control peptide, TAT(47-57) (TAT, n=8), by osmotic pump began 3 days after transplantation and continued for the remaining 4 weeks. epsilonV1-2 treatment significantly improved the beating score throughout the treatment. Infiltration of macrophages and T cells into the cardiac grafts was significantly reduced and parenchymal fibrosis was decreased in animals treated with epsilonV1-2 as compared with control treatment. Finally, the rise in pro-fibrotic cytokine, TGF-beta and monocyte recruiting chemokine MCP-1 levels was almost abolished by epsilonV1-2 treatment, whereas the rise in PDGF-BB level was unaffected. These data suggest that epsilonPKC activity contributes to the chronic immune response in cardiac allograft and that an epsilonPKC-selective inhibitor, such as epsilonV1-2, could augment current therapeutic strategies to suppress inflammation and prolong graft survival in humans.
Koyanagi
Tomoyoshi
T
Department of Chemical and Systems Biology, Stanford University School of Medicine CCSR, Rm 3145A, 269 Campus Drive Stanford, CA 94305-5174, USA.
Noguchi
Kenichiro
K
Ootani
Akifumi
A
Inagaki
Koichi
K
Robbins
Robert C
RC
Mochly-Rosen
Daria
D
D000818:Animals; D002908:Chronic Disease; D016572:Cyclosporine / Q000627:therapeutic use; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000209:etiology; D006085:Graft Survival / Q000187:drug effects; D006333:Heart Failure / Q000473:pathology / Q000628:therapy*; D016027:Heart Transplantation / Q000009:adverse effects* / Q000473:pathology; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000188:drug therapy* / Q000209:etiology*; D020556:Neutrophil Infiltration / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects; D016042:Transplantation, Heterotopic / Q000009:adverse effects
D007166:Immunosuppressive Agents; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; C448318:epsilonV1-2 peptide; D016572:Cyclosporine; D051744:Protein Kinase C-epsilon