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Published 26 September 2005. doi:10.1083/jcb.200505022
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 7, 1079-1090
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Article

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

Muniswamy Madesh1,2, Brian J. Hawkins1, Tatyana Milovanova1, Cunnigaiper D. Bhanumathy3, Suresh K. Joseph3, Satish P. RamachandraRao4, Kumar Sharma4, Tomohiro Kurosaki5, and Aron B. Fisher1

1 Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, PA 19104
2 Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104
3 Department of Pathology, Anatomy, and Cell Biology
4 Dorrance Hamilton Research Laboratories, Thomas Jefferson University, Philadelphia, PA 19107
5 Laboratory for Lymphocyte Differentiation, Institute of Physical and Chemical Research, Research Center for Allergy and Immunology, Turumi-ku, Yokohama 230-0045, Japan

Correspondence to Muniswamy Madesh: madeshm{at}mail.med.upenn.edu

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 O2.–-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 [Ca2+]i buffering. This study provides evidence that O2.– facilitates an InsP3R-linked apoptotic cascade and may serve a critical function in I/R injury and inflammation.

Abbreviations used in this paper: 2-APB, 2-aminoethoxydiphenyl borate; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetracetate; [Ca2+]i, intracellular calcium; {Delta}{Psi}m, mitochondrial membrane potential; DCF, dichlorofluorescein; DPI, diphenyleneiodonium; ECM, extracellular medium; GPCR, G protein–coupled receptor; InsP3, inositol 1,4,5-trisphosphate; InsP3R, InsP3 receptor; I/R, ischemia/reperfusion; KO, knockout; LPS, lipopolysaccharide; MPTP, mitochondrial permeability transition pore; PI, propidium iodide; PMVEC, pulmonary microvascular endothelial cell; ROS, reactive oxygen species; SOD, superoxide dismutase; t-BuOOH, tert-butyl hydroperoxide; Tg, thapsigargin; TKO, triple KO; TMRE, tetramethylrhodamine, ethyl ester, perchlorate.


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