Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes

Terry L. Vanden Hoek, Lance B. Becker, Zuohui Shao, Changqing Li, Paul T. Schumacker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

602 Scopus citations

Abstract

Reactive oxygen species (ROS) have been proposed to participate in the induction of cardiac preconditioning. However, their source and mechanism of induction are unclear. We tested whether brief hypoxia induces preconditioning by augmenting mitochondrial generation of ROS in chick cardiomyocytes. Cells were preconditioned with 10 min of hypoxia, followed by 1 h of simulated ischemia and 3 h of reperfusion. Preconditioning decreased cell death from 47 ± 3% to 14 ± 2%. Return of contraction was observed in 3/3 preconditioned versus 0/6 non-preconditioned experiments. During induction, ROS oxidation of the probe dichlorofluorescin (sensitive to H2O2) increased ~2.5-fold. As a substitute for hypoxia, the addition of H2O2 (15 μmol/liter) during normoxia ia also induced preconditioning-like protection. Conversely, the ROS signal during hypoxia was attenuated with the thiol reductant 2-mercaptopropionyl glycine, the cytosolic Cu,Zn-superoxide dismutase inhibitor diethyldithiocarbamic acid, and the anion channel inhibitor 4,4'-diisothiocyanato-stilbene-2,2'-disulfonate, all of which also abrogated protection. ROS generation during hypoxia was attenuated by myxothiazol, but not by diphenyleneiodonium or the nitric-oxide synthase inhibitor L-nitroarginine. We conclude that hypoxia increases mitochondrial superoxide generation which initiates preconditioning protection. Furthermore, mitochondrial anion channels and cytosolic dismutation to H2O2 may be important steps for oxidant induction of hypoxic preconditioning.

Original languageEnglish (US)
Pages (from-to)18092-18098
Number of pages7
JournalJournal of Biological Chemistry
Volume273
Issue number29
DOIs
StatePublished - Jul 17 1998

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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