Early inhibition of caspase-3 activity lessens the development of graft coronary artery disease

Leora B. Balsam, G. Kimia Mokhtari, Sophie Jones, Shannon Peterson, E. Grant Hoyt, Theo Kofidis, Masashi Tanaka, David T. Cooke, Robert C. Robbins

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Background: The role of apoptosis in the development of graft coronary artery disease (GCAD) is poorly understood. We have previously shown that early overexpression of the anti-apoptotic protein Bcl-2 lessens the development of GCAD. We hypothesized that early inhibition of apoptosis with a caspase-3 inhibitor would also lessen the development of GCAD. Methods: Heterotopic heart transplantation was performed in 4 groups of rats. Donor hearts were pretreated with 50 μg DEVD-CHO, a cell-permeable caspase-3 inhibitor, or vehicle. Recipient animals were pretreated with 1.7 mg/kg intraperitoneal DEVD-CHO or vehicle. Animals were treated with 7.5 mg/kg/d cyclosporine for 10 days to prevent acute rejection. On post-operative day 90, the animals were sacrificed and the transplanted hearts were assessed morphometrically for evidence of GCAD. Results: At 90 days, intimal proliferation was significantly higher in vehicle treated animals than in inhibitor treated animals. Moreover, the percentage of vessels with high-grade occlusion (>50%) was also lower in inhibitor treated animals. Conclusions: Early inhibition of caspase-3 activity with cell-permeable DEVD-CHO lessens the development of GCAD. Caspase-3 inhibition may be a useful strategy for prevention of GCAD in clinical transplantation.

Original languageEnglish (US)
Pages (from-to)827-832
Number of pages6
JournalJournal of Heart and Lung Transplantation
Volume24
Issue number7
DOIs
StatePublished - Jul 2005
Externally publishedYes

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

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