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Effect of Graded Hypoxia on High-Affinity Ca2+-ATPase Activity in Cortical Neuronal Nuclei of Newborn Piglets

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Previous studies have shown that nuclear calcium signals control a variety of nuclear functions including gene transcription, DNA synthesis, DNA repair and nuclear envelope breakdown. The present study tested the hypothesis that the activity of the neuronal nuclear high affinity Ca2+-ATPase increases as a function of decreased energy metabolism in the cerebral cortex. Studies were performed in 11 ventilated newborn piglets, age 3–5 days, divided into normoxic (Nx, n = 4) and hypoxic (Hx, n = 7) groups. The animals were exposed to a single FiO2 in the range from 0.21 to 0.05 for one hr. Cerebral tissue hypoxia was confirmed biochemically by determining brain tissue ATP and phosphocreatine levels. Neuronal nuclei were isolated and the high-affinity Ca2+-ATPase activity determined. During graded hypoxia, cerebral tissue ATP decreased from 4.80 ± 0.58 (normoxic) to 1.03 ± 0.38 (ranging from 0.61–1.63) μmol/g brain (p < 0.05) and PCr decreased from 3.94 ± 0.75 (normoxic) to 0.99 ± 0.27 (ranging from 0.50 to 1.31) μmol/g brain (p < 0.05). The total high affinity Ca2+-ATPase activity in the hypoxic nuclei increased and ranged from 541 to 662 nmol/mg protein/hr, compared to activity in normoxic group of 327 to 446 nmol/mg protein/hr. During graded hypoxia, the level of nuclear high affinity Ca2+-ATPase activity correlated inversely with ATP (r = 0.91) and PCr levels (r = 0.82), with activity increasing as tissue high energy phosphates decreased. The results demonstrate that the decrease in cerebral energy metabolism during hypoxia is linearly correlated with an increase in activity of high affinity Ca2+-ATPase in cerebral cortical nuclei from immature brain. We propose that increased nuclear membrane high affinity Ca2+-ATPase activity, leading to increased nuclear Ca2+, will result in altered expression of apoptotic genes that could initiate programmed neuronal death.

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  1. Department of Pediatrics, MCP Hahnemann University and St. Christopher's Hospital for Children, Philadelphia, PA

    Om Prakash Mishra & Maria Delivoria-Papadopoulos

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Mishra, O.P., Delivoria-Papadopoulos, M. Effect of Graded Hypoxia on High-Affinity Ca2+-ATPase Activity in Cortical Neuronal Nuclei of Newborn Piglets. Neurochem Res 26, 1335–1341 (2001). https://doi.org/10.1023/A:1014205702905

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