Heterozygous HIF-1α deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia

被引:309
作者
Peng, Ying-Jie
Yuan, Guoxiang
Ramakrishnan, Deviprasadh
Sharma, Suresh D.
Bosch-Marce, Marta
Kumar, Ganesh K.
Semenza, Gregg L.
Prabhakar, Nanduri R.
机构
[1] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA
[3] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Sch Med, Dept Pediat, Inst Cell Engn,Vasc Biol Program, Baltimore, MD 21205 USA
[5] Johns Hopkins Univ, Sch Med, Dept Med, Inst Cell Engn,Vasc Biol Program, Baltimore, MD 21205 USA
[6] Johns Hopkins Univ, Sch Med, Dept Oncol, Inst Cell Engn,Vasc Biol Program, Baltimore, MD 21205 USA
[7] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Inst Cell Engn,Vasc Biol Program, Baltimore, MD 21205 USA
来源
JOURNAL OF PHYSIOLOGY-LONDON | 2006年 / 577卷 / 02期
关键词
INDUCIBLE FACTOR 1-ALPHA; SLEEP-APNEA; VENTILATORY RESPONSES; OXIDATIVE STRESS; PC12; CELLS; EXPRESSION; FACTOR-1; BRAIN; CHEMOREFLEXES; ANGIOGENESIS;
D O I
10.1113/jphysiol.2006.114033
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Chronic intermittent hypoxia (CIH) occurs in patients with sleep apnoea and has adverse effects on multiple physiological functions. Previous studies have shown that reflexes arising from carotid bodies mediate CIH-evoked cardio-respiratory responses, and reactive oxygen species (ROS) play important roles in eliciting systemic responses to CIH. Very little is known about the molecular mechanisms underlying CIH. The transcriptional activator hypoxia-inducible factor-1 (HIF-1) mediates a broad range of cellular and systemic responses to hypoxia, and HIF-1 is activated in cell cultures exposed to IH. In the present study we examined whether CIH activates HIF-1 and if so whether it contributes to cardio-respiratory responses and ROS generation in mice. Experiments were performed on male littermate wild-type (WT) and heterozygous (HET) mice partially deficient in HIF-1 alpha, the O-2 regulated subunit of the HIF-1 complex. Both groups of mice were exposed to either 10 days of CIH (15 s of hypoxia followed by 5 min of normoxia, 9 episodes h(-1), 8 h day(-1)) or to 10 days of 21% O-2 (controls). Carotid body response to hypoxia was augmented, and acute intermittent hypoxia (AIH) induced sensory long-term facilitation (sLTF) of the chemoreceptor activity in CIH-exposed WT mice. In striking contrast, hypoxic sensory response was unaffected and AIH was ineffective in eliciting sLTF in CIH-exposed HET mice. Analysis of cardio-respiratory responses in CIH-exposed WT mice revealed augmented hypoxic ventilatory response, LTF of breathing, elevated blood pressures and increased plasma noradrenaline. In striking contrast these responses were either absent or attenuated in HET mice exposed to CIH. In CIH-exposed WT mice, ROS were elevated and this response was absent in HET mice. Manganese (III) tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride, a potent scavenger of superoxide, not only prevented CIH-induced increases in ROS but also CIH-evoked HIF-1 alpha up-regulation in WT mice. These results indicate that: (a) HIF-1 activation is critical for eliciting CIH-induced carotid body-mediated cardio-respiratory responses; (b) CIH increases ROS; and (c) the effects of CIH involve complex positive interactions between HIF-1 and ROS.
引用
收藏
页码:705 / 716
页数:12
相关论文
共 35 条
  • [1] Bergeron M, 2000, ANN NEUROL, V48, P285, DOI 10.1002/1531-8249(200009)48:3<285::AID-ANA2>3.3.CO
  • [2] 2-#
  • [3] BUELKESAM J, 1978, LAB ANIM SCI, V28, P157
  • [4] Expression of hypoxia-inducible factor-1α in the brain of rats during chronic hypoxia
    Chávez, JC
    Agani, F
    Pichiule, P
    LaManna, JC
    [J]. JOURNAL OF APPLIED PHYSIOLOGY, 2000, 89 (05) : 1937 - 1942
  • [5] Cistulli PA., 1994, Sleep and Breathing, P405
  • [6] CHEMOREFLEXES IN BREATHING
    DEJOURS, P
    [J]. PHYSIOLOGICAL REVIEWS, 1962, 42 (03) : 335 - &
  • [7] Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients
    Dyugovskaya, L
    Lavie, P
    Lavie, L
    [J]. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2002, 165 (07) : 934 - 939
  • [8] CAROTID CHEMORECEPTORS, SYSTEMIC BLOOD-PRESSURE, AND CHRONIC EPISODIC HYPOXIA MIMICKING SLEEP-APNEA
    FLETCHER, EC
    LESSKE, J
    BEHM, R
    MILLER, CC
    STAUSS, H
    UNGER, T
    [J]. JOURNAL OF APPLIED PHYSIOLOGY, 1992, 72 (05) : 1978 - 1984
  • [9] METABOLISM AND VENTILATION IN ACUTE-HYPOXIA - A COMPARATIVE-ANALYSIS IN SMALL MAMMALIAN-SPECIES
    FRAPPELL, P
    LANTHIER, C
    BAUDINETTE, RV
    MORTOLA, JP
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1992, 262 (06): : R1040 - R1046
  • [10] Interactions among metabolic rate, hypoxia, and control of breathing
    Gautier, H
    [J]. JOURNAL OF APPLIED PHYSIOLOGY, 1996, 81 (02) : 521 - 527