TY - JOUR
T1 - Selective role for superoxide in InsP3 receptor-mediated mitochondrial dysfunction and endothelial apoptosis
AU - Madesh, Muniswamy
AU - Hawkins, Brian J.
AU - Milovanova, Tatyana
AU - Bhanumathy, Cunnigaiper D.
AU - Joseph, Suresh K.
AU - RamachandraRao, Satish P.
AU - Sharma, Kumar
AU - Kurosaki, Tomohiro
AU - Fisher, Aron B.
PY - 2005/9/26
Y1 - 2005/9/26
N2 - 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.
AB - 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.
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U2 - 10.1083/jcb.200505022
DO - 10.1083/jcb.200505022
M3 - Article
C2 - 16186254
AN - SCOPUS:25444525139
SN - 0021-9525
VL - 170
SP - 1079
EP - 1090
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 7
ER -