Early inhibition of caspase-3 activity lessens the development of graft coronary artery disease.
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 microg 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.
Balsam
Leora B
LB
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California 94305, USA. lbalsam@stanford.edu
Mokhtari
G Kimia
GK
Jones
Sophie
S
Peterson
Shannon
S
Hoyt
E Grant
EG
Kofidis
Theo
T
Tanaka
Masashi
M
Cooke
David T
DT
Robbins
Robert C
RC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D061945:Caspase Inhibitors; D003324:Coronary Artery Disease / Q000517:prevention & control*; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D015870:Gene Expression; D019254:Genes, bcl-2; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D016027:Heart Transplantation; D008297:Male; D009842:Oligopeptides / Q000627:therapeutic use*; D051381:Rats; D011912:Rats, Inbred ACI
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C108637:aspartyl-glutamyl-valyl-aspartal; C505410:Casp3 protein, rat; D053148:Caspase 3