Reduced SERCA activity underlies dysregulation of Ca²⁺ homeostasis under atmospheric O₂ levels

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.