Reduced SERCA activity underlies dysregulation of Ca homeostasis under atmospheric O levels.

Unregulated increases in cellular Ca homeostasis are a hallmark of pathophysiological conditions and a key trigger of cell death. Endothelial cells cultured under physiologic O conditions (5% O) exhibit a reduced cytosolic Ca response to stimulation. The mechanism for reduced plateau [Ca] upon stimulation was due to increased sarco/endoplasmic reticulum Ca ATPase (SERCA)-mediated reuptake rather than changes in Ca influx capacity. Agonist-stimulated phosphorylation of the SERCA regulatory protein phospholamban was increased in cells cultured under 5% O. Elevation of cytosolic and mitochondrial [Ca] and cell death after prolonged ionomycin treatment, as a model of Ca overload, were lower when cells were cultured long-term under 5% compared with 18% O. 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 [Ca], 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 Ca homeostasis under atmospheric O levels.