Pharmacological inhibition of epsilon PKC suppresses chronic inflammation in murine cardiac transplantation model

Tomoyoshi Koyanagi, Kenichiro Noguchi, Akifumi Ootani, Koichi Inagaki, Robert C. Robbins, Daria Mochly-Rosen

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Epsilon protein kinase C (εPKC) 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 εPKC inhibition beginning 3 days after transplantation suppress allograft rejection and improve cardiac transplantation using a murine heterotopic transplantation model. Hearts of FVB mice (H-2q) were transplanted into C57BL/6 mice (H-2b). Delivery of the εPKC inhibitor, TAT47-57-εV1-2 (εV1-2, n = 9, 20 mg/kg/day), or the carrier control peptide, TAT47-57 (TAT, n = 8), by osmotic pump began 3 days after transplantation and continued for the remaining 4 weeks. εV1-2 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 εV1-2 as compared with control treatment. Finally, the rise in pro-fibrotic cytokine, TGF-β and monocyte recruiting chemokine MCP-1 levels was almost abolished by εV1-2 treatment, whereas the rise in PDGF-BB level was unaffected. These data suggest that εPKC activity contributes to the chronic immune response in cardiac allograft and that an εPKC-selective inhibitor, such as εV1-2, could augment current therapeutic strategies to suppress inflammation and prolong graft survival in humans.

Original languageEnglish (US)
Pages (from-to)517-522
Number of pages6
JournalJournal of Molecular and Cellular Cardiology
Volume43
Issue number4
DOIs
StatePublished - Oct 2007
Externally publishedYes

Keywords

  • Fibrosis
  • Inflammation
  • Protein kinase C
  • Signal transduction
  • Transplantation

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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