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.
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.
Authors: Juliet A Emamaullee; Joy Davis; Rena Pawlick; Christian Toso; Shaheed Merani; Sui-Xiong Cai; Ben Tseng; A M James Shapiro Journal: Diabetes Date: 2010-03-23 Impact factor: 9.461