Cell death during ischemia: Relationship to mitochondrial depolarization and ROS generation

Jacques Levraut, Hirotaro Iwase, Z. H. Shao, Terry L. Vanden Hoek, Paul T. Schumacker*

*Corresponding author for this work

Research output: Contribution to journalArticle

162 Scopus citations

Abstract

Ischemia-reperfusion injury induces cell death, but the responsible mechanisms are not understood. This study examined mitochondrial depolarization and cell death during ischemia and reperfusion. Contracting cardiomyocytes were subjected to 60-min ischemia followed by 3-h reperfusion. Mitochondrial membrane potential (Δψm) was assessed with tetramethylrhodamine methyl ester. During ischemia, Δψm decreased to 24 ± 5.5% of baseline, but no recovery was evident during reperfusion. Cell death assessed by Sytox Green was minimal during ischemia but averaged 66 ± 7% after 3-h reperfusion. Cyclosporin A, an inhibitor of mitochondrial permeability transition, was not protective. However, pharmacological antioxidants attenuated the fall in Δψm during ischemia and cell death after reperfusion and decreased lipid peroxidation as assessed with C11-BODIPY. Cell death was also attenuated when residual O2 was scavenged from the perfusate, creating anoxic ischemia. These results suggested that reactive oxygen species (ROS) were important for the decrease in Δψm during ischemia. Finally, 143B-ρ osteosarcoma cells lacking a mitochondrial electron transport chain failed to demonstrate a depletion of Δψm during ischemia and were significantly protected against cell death during reperfusion. Collectively, these studies identify a central role for mitochondrial ROS generation during ischemia in the mitochondrial depolarization and subsequent cell death induced by ischemia and reperfusion in this model.

Original languageEnglish (US)
Pages (from-to)H549-H558
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume284
Issue number2 53-2
DOIs
StatePublished - Feb 1 2003

Keywords

  • Hypoxia
  • Oxidants
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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