Magnesium Deficiency Causes Loss of Response to Intermittent Hypoxia in Paraganglion Cells
Magnesium Deficiency Causes Loss of Response to Intermittent Hypoxia in Paraganglion Cells
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DOI：
10.1074/jbc.m109.004424
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发表时间：
2009-07-10
影响因子：
4.8
通讯作者：
Sogawa, Kazuhiro
中科院分区：
文献类型：
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作者：
Torii, Satoru;Kobayashi, Kentaro;Sogawa, Kazuhiro
镁缺乏被认为是导致许多与年龄有关的疾病的原因。低氧诱导因子1 α（HIF-1 α）是低氧反应的主要调节因子。在这里，我们表明，低镁血症抑制活性氧（ROS）诱导的HIF-1 α的肾上腺髓质和颈动脉体的副神经节细胞的活动。在低镁培养基中培养的PC 12细胞中，用氯化钴（CoCl 2）处理或暴露于间歇性缺氧，ROS介导的HIF-1 α活性被抑制。这种抑制是由于NF-κ B激活引起的抑制性PAS（Per/Arnt/Sim）结构域蛋白（IPAS）的上调，这主要是通过T型钙通道的ROS和钙内流引起的。由于IPAS的上调，CoCl 2注射对HIF-1靶点酪氨酸羟化酶的诱导在镁缺乏小鼠的肾上腺髓质中受到抑制。此外，在镁缺乏小鼠的颈动脉体，氯化钴和慢性间歇性缺氧未能增强酪氨酸羟化酶的表达。这些结果表明，血清镁水平是ROS诱导的缺氧反应的关键决定因素。
Magnesium deficiency is suggested to contribute to many age-related diseases. Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is known to be a master regulator of hypoxic response. Here we show that hypomagnesemia suppresses reactive oxygen species (ROS)-induced HIF-1 alpha activity in paraganglion cells of the adrenal medulla and carotid body. In PC12 cells cultured in the low magnesium medium and treated with cobalt chloride (CoCl2) or exposed to intermittent hypoxia, ROS-mediated HIF-1 alpha activity was suppressed. This suppression was due to up-regulation of inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS) that was caused by NF-kappa B activation, which resulted from ROS and calcium influx mainly through the T-type calcium channels. Induction of tyrosine hydroxylase, a target of HIF-1, by CoCl2 injection was suppressed in the adrenal medulla of magnesium-deficient mice because of up-regulation of IPAS. Also in the carotid body of magnesium-deficient mice, CoCl2 and chronic intermittent hypoxia failed to enhance the tyrosine hydroxylase expression. These results demonstrate that serum magnesium levels are a key determinant for ROS-induced hypoxic responses.