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Unregulated increases in cellular Ca2+ homeostasis are a hallmark of pathophysiological conditions and a key trigger of cell death. Endothelial cells cultured under physiologic O2 conditions (5% O2) exhibit a reduced cytosolic Ca2+ response to stimulation. The mechanism for reduced plateau [Ca2+]i upon stimulation was due to increased sarco/endoplasmic reticulum Ca2+ ATPase (SERCA)-mediated reuptake rather than changes in Ca2+ influx capacity. Agonist-stimulated phosphorylation of the SERCA regulatory protein phospholamban was increased in cells cultured under 5% O2. Elevation of cytosolic and mitochondrial [Ca2+] and cell death after prolonged ionomycin treatment, as a model of Ca2+ overload, were lower when cells were cultured long-term under 5% compared with 18% O2. This protection was abolished by cotreatment with the SERCA inhibitor cyclopiazonic acid. Taken together, these results demonstrate that culturing cells under hyperoxic conditions reduces their ability to efficiently regulate [Ca2+]i, resulting in greater sensitivity to cytotoxic stimuli.-Keeley, T. P., Siow, R. C. M., Jacob, R., Mann, G. E. Reduced SERCA activity underlies dysregulation of Ca2+ homeostasis under atmospheric O2 levels.

Original publication




Journal article


FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Publication Date





2531 - 2538


King's British Heart Foundation Centre for Research Excellence, School of Cardiovascular Medicine and Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.


Mitochondria, Humans, Hyperoxia, Oxygen, Calcium, Indoles, Ionomycin, Calcium-Binding Proteins, Cell Death, Calcium Signaling, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Human Umbilical Vein Endothelial Cells