Selective role for superoxide in InsP3 receptor-mediated mitochondrial dysfunction and endothelial apoptosis.
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.
Madesh
Muniswamy
M
Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. madeshm@mail.med.upenn.edu
Hawkins
Brian J
BJ
Milovanova
Tatyana
T
Bhanumathy
Cunnigaiper D
CD
Joseph
Suresh K
SK
Ramachandrarao
Satish P
SP
Sharma
Kumar
K
Kurosaki
Tomohiro
T
Fisher
Aron B
AB
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D020169:Caspases / Q000096:biosynthesis; D002478:Cells, Cultured; D002645:Chickens; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism* / Q000494:pharmacology
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008070:Lipopolysaccharides; D018160:Receptors, Cytoplasmic and Nuclear; D013481:Superoxides; D020169:Caspases; D002118:Calcium