Magnesium deficiency causes loss of response to intermittent hypoxia in paraganglion cells.
Magnesium deficiency is suggested to contribute to many age-related diseases. Hypoxia-inducible factor 1alpha (HIF-1alpha) is known to be a master regulator of hypoxic response. Here we show that hypomagnesemia suppresses reactive oxygen species (ROS)-induced HIF-1alpha 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 (CoCl(2)) or exposed to intermittent hypoxia, ROS-mediated HIF-1alpha activity was suppressed. This suppression was due to up-regulation of inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS) that was caused by NF-kappaB 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 CoCl(2) 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, CoCl(2) 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.
Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan.
Satoru
S
Torii
Kentaro
K
Kobayashi
Masayuki
M
Takahashi
Kasumi
K
Katahira
Kenji
K
Goryo
Natsuki
N
Matsushita
Ken-Ichi
K
Yasumoto
Yoshiaki
Y
Fujii-Kuriyama
Kazuhiro
K
Sogawa
D000818:Animals; D002118:Calcium / Q000378:metabolism; D005724:Ganglia / Q000166:cytology / Q000378:metabolism*; D000860:Hypoxia; D008275:Magnesium Deficiency / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016716:PC12 Cells; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014446:Tyrosine 3-Monooxygenase; D002118:Calcium