Intracellular signaling by reactive oxygen species during hypoxia in cardiomyocytes

Jacques Duranteau, Navdeep S. Chandel, Andre Kulisz, Zuohui Shao, Paul T. Schumacker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

557 Scopus citations

Abstract

Cardiomyocytes suppress contraction and O2 consumption during hypoxia. Cytochrome oxidase undergoes a decrease in V(max) during hypoxia, which could alter mitochondrial redox and increase generation of reactive oxygen species (ROS). We therefore tested whether ROS generated by mitochondria act as second messengers in the signaling pathway linking the detection of O2 with the functional response. Contracting cardiomyocytes were superfused under controlled O2 conditions while fluorescence imaging of 2,7- dichlorofluorescein (DCF) was used to assess ROS generation. Compared with normoxia (PO2 ~ 107 torr, 15% O2), graded increases in DCF fluorescence were seen during hypoxia, with responses at PO2 = 7 torr > 20 torr > 35 torr. The antioxidants 2-mercaptopropionyl glycine and 1,10-phenanthroline attenuated these increases and abolished the inhibition of contraction. Superfusion of normoxic cells with H2O2 (25 μM) for >60 min mimicked the effects of hypoxia by eliciting decreases in contraction that were reversible after washout of H2O2. To test the role of cytochrome oxidase, sodium azide (0.75-2 μM) was added during normoxia to reduce the V(max) of the enzyme. Azide produced graded increases in ROS signalling, accompanied by graded decreases in contraction that were reversible. These results demonstrate that mitochondria respond to graded hypoxia by increasing the generation of ROS and suggest that cytochrome oxidase may contribute to this O2 sensing.

Original languageEnglish (US)
Pages (from-to)11619-11624
Number of pages6
JournalJournal of Biological Chemistry
Volume273
Issue number19
DOIs
StatePublished - May 8 1998

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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