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.
FASEB J. 2018 May;32(5):2531-2538. doi: 10.1096/fj.201700685RRR. Epub 2017 Dec 22.
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.
细胞内钙离子稳态的不受调节的增加是病理生理状态的标志，也是细胞死亡的关键触发因素。在生理氧条件（5%O）下培养的内皮细胞对刺激的细胞质 Ca 反应降低。刺激时平台 [Ca] 降低的机制是由于肌浆/内质网 Ca ATP 酶（SERCA）介导的再摄取增加，而不是 Ca 流入能力的变化。在 5%O 下培养的细胞中，激动剂刺激的 SERCA 调节蛋白磷酸化酶的磷酸化增加。与在 18%O 下相比，在用延长的离子霉素处理作为 Ca 超载模型后，细胞在 5%O 下长期培养后细胞质和线粒体 [Ca] 升高和细胞死亡降低。用 SERCA 抑制剂环匹阿尼酸共同处理会消除这种保护作用。总之，这些结果表明，在高氧条件下培养细胞会降低其有效调节 [Ca] 的能力，从而使细胞对细胞毒性刺激更敏感。-Keeley, T. P., Siow, R. C. M., Jacob, R., Mann, G. E. 在大气 O 水平下，Ca 稳态失调的基础是 SERCA 活性降低。
