Magnesium Deficiency Causes Loss of Response to Intermittent Hypoxia in Paraganglion Cells*

  1. Satoru Torii‡,
  2. Kentaro Kobayashi‡,
  3. Masayuki Takahashi‡,
  4. Kasumi Katahira‡,
  5. Kenji Goryo‡,
  6. Natsuki Matsushita§,
  7. Ken-ichi Yasumoto‡,
  8. Yoshiaki Fujii-Kuriyama and
  9. Kazuhiro Sogawa‡,1
  1. From the ‡Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai 980-8578,
  2. the §Department of Biochemistry and Molecular Genetics, Graduate School of Medicine, University of Ehime, Matsuyama 791-0295, and
  3. Center for Tsukuba Advanced Research Alliance and the Solution-Oriented Research for Science and Technology (SORST) Project, Japan Science and Technology Agency, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan
  1. 1 To whom correspondence should be addressed. Tel.: 81-22-795-6590; Fax: 81-22-795-6594; E-mail: sogawa{at}mail.tains.tohoku.ac.jp.

Abstract

Magnesium deficiency is suggested to contribute to many age-related diseases. Hypoxia-inducible factor 1α (HIF-1α) is known to be a master regulator of hypoxic response. Here we show that hypomagnesemia suppresses reactive oxygen species (ROS)-induced HIF-1α 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-1α activity was suppressed. This suppression was due to up-regulation of inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS) that was caused by NF-κB 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.

Footnotes

  • ↵* This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

  • ↵Graphic The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2 and Figs. S1–S5.

  • ↵3 S. Torii, K. Kobayashi, M. Takahashi, K. Katahira, K. Goryo, N. Matsushita, K.-I. Yasumoto, Y. Fujii-Kuriyama, and K. Sogawa, unpublished data.

  • ↵2 The abbreviations used are:

    HIF

    hypoxia-inducible factor

    ROS

    reactive oxygen species

    TH

    tyrosine hydroxylase

    HRE

    hypoxia response element

    AM

    adrenal medulla

    CB

    carotid body

    IH

    intermittent hypoxia

    CIH

    chronic IH

    OSA

    obstructive sleep apnea

    PAS

    Per/Arnt/Sim

    IPAS

    inhibitory PAS domain protein

    DMEM

    Dulbecco's modified Eagle's medium

    PMA

    phorbol 12-myristate 13-acetate

    NAC

    N-acetyl-l-cysteine

    RT

    reverse transcription

    siRNA

    small interfering RNA

    PI3K

    phosphatidylinositol 3-kinase

    PKC

    protein kinase C.

    • Received April 6, 2009.
    • Revision received May 7, 2009.
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  1. First Published on May 11, 2009, doi: 10.1074/jbc.M109.004424 July 10, 2009 The Journal of Biological Chemistry, 284, 19077-19089.
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