Abstract
Myocardial ischemia and reperfusion lead to myocyte cell death, at least in part, by an apoptotic mechanism. Caspases are a conserved family of proteases that play an essential role in the execution of apoptosis; however, their potential contribution to ischemic myocardial cell death is largely unknown. To examine their role in this process, we subjected rabbits to 30 min of coronary artery occlusion followed by 3 h of reperfusion. Immunoblot analyses revealed that caspases-2, -3 and -7 were proteolytically activated during myocardial ischemia and reperfusion in vivo. In addition, the well-characterized caspase substrate poly(ADP-ribose) polymerase (PARP) was selectively cleaved into its signature apoptotic fragment in ischemic/reperfused myocardium. Systemic administration of the broad-spectrum caspase inhibitor acetyl-Tyr-Val-Ala-Asp chloromethylketone (YVAD-cmk, 4.8 mg/kg) partially blocked caspase activation and dramatically reduced the percentage of terminal dUTP deoyxynucleotidyl-transferase nick end-labeling (TUNEL)-positive myocyte nuclei in the infarct region (3.9 ± 0.8% v 13.0 ± 2.2% in control animals, P = 0.012). Moreover, YVAD-cmk reduced myocardial infarct size by appropriately 31% (31.1 ± 3.3% v 45.3 ± 4.9% in control animals, P = 0.032). These results indicate that caspases are critical mediators of myocardial injury induced by ischemia and reperfusion in vivo, and they suggest that caspase inhibition may be therapeutically beneficial in myocardial infarction.
Original language | English (US) |
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Pages (from-to) | 1709-1715 |
Number of pages | 7 |
Journal | Journal of Molecular and Cellular Cardiology |
Volume | 31 |
Issue number | 9 |
DOIs | |
State | Published - Sep 1999 |
Funding
We are indebted to Dr. Junying Yuan for the caspase-7 monoclonal antibody and to Dr Rick Kitsis for his critical reading of the manuscript. This work was supported in part by an NIH Mentored Clinical Scientist Development Award (to VLC), an institutional research grant to Northwestern University from the Howard Hughes Medical Institute (to VLC), and a research grant from Northwestern University Medical School (to TAH).
Keywords
- Apoptosis
- Ischemia
- Myocardial infarction
- Proteases
- Reperfusion injury
ASJC Scopus subject areas
- Molecular Biology
- Cardiology and Cardiovascular Medicine