Selective role for superoxide in InsP3 receptor-mediated mitochondrial dysfunction and endothelial apoptosis

Muniswamy Madesh, Brian J. Hawkins, Tatyana Milovanova, Cunnigaiper D. Bhanumathy, Suresh K. Joseph, Satish P. RamachandraRao, Kumar Sharma, Tomohiro Kurosaki, Aron B. Fisher

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Reactive oxygen species (ROS) play a divergent role in both cell survival and cell death during ischemia/reperfusion (I/R) injury and associated inflammation. In this study, ROS generation by activated macrophages evoked an intracellular Ca2+([Ca2+]i) transient in endothelial cells that was ablated by a combination of superoxide dismutase and an anion channel blocker. [Ca2+]i store depletion, but not extracellular Ca2+ chelation, prevented [Ca2+] i elevation in response to O2.- that was inositol 1,4,5-trisphosphate (InsP3) dependent, and cells lacking the three InsP3 receptor (InsP3R) isoforms failed to display the [Ca2+]i transient. Importantly, the O 2.- -triggered Ca2+ mobilization preceded a loss in mitochondrial membrane potential that was independent of other oxidants and mitochondrially derived ROS. Activation of apoptosis occurred selectively in response to O2.- and could be prevented by [Ca 2+]i buffering. This study provides evidence that O 2.- facilitates an InsP3R-linked apoptotic cascade and may serve a critical function in I/R injury and inflammation.

Original languageEnglish (US)
Pages (from-to)1079-1090
Number of pages12
JournalJournal of Cell Biology
Volume170
Issue number7
DOIs
StatePublished - Sep 26 2005

    Fingerprint

ASJC Scopus subject areas

  • Cell Biology

Cite this

Madesh, M., Hawkins, B. J., Milovanova, T., Bhanumathy, C. D., Joseph, S. K., RamachandraRao, S. P., Sharma, K., Kurosaki, T., & Fisher, A. B. (2005). Selective role for superoxide in InsP3 receptor-mediated mitochondrial dysfunction and endothelial apoptosis. Journal of Cell Biology, 170(7), 1079-1090. https://doi.org/10.1083/jcb.200505022