Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivo

Thomas A. Holly, Andjela Drincic, Youngsup Byun, Sakie Nakamura, Kathleen Harris, Francis J. Klocke, Vincent L. Cryns

Research output: Contribution to journalArticlepeer-review

253 Scopus citations

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 languageEnglish (US)
Pages (from-to)1709-1715
Number of pages7
JournalJournal of Molecular and Cellular Cardiology
Volume31
Issue number9
DOIs
StatePublished - Sep 1999
Externally publishedYes

Keywords

  • Apoptosis
  • Ischemia
  • Myocardial infarction
  • Proteases
  • Reperfusion injury

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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