PMID- 16973705 OWN - NLM STAT- MEDLINE DCOM- 20070126 LR - 20181113 IS - 0022-3751 (Print) IS - 1469-7793 (Electronic) IS - 0022-3751 (Linking) VI - 577 IP - Pt 2 DP - 2006 Dec 1 TI - Heterozygous HIF-1alpha deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. PG - 705-16 AB - 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-1alpha, the O2 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% O2 (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-1alpha 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. FAU - Peng, Ying-Jie AU - Peng YJ AD - Department of Physiology & Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44109, USA. FAU - Yuan, Guoxiang AU - Yuan G FAU - Ramakrishnan, Deviprasadh AU - Ramakrishnan D FAU - Sharma, Suresh D AU - Sharma SD FAU - Bosch-Marce, Marta AU - Bosch-Marce M FAU - Kumar, Ganesh K AU - Kumar GK FAU - Semenza, Gregg L AU - Semenza GL FAU - Prabhakar, Nanduri R AU - Prabhakar NR LA - eng GR - P01 HL025830/HL/NHLBI NIH HHS/United States GR - HL-25830/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20060914 PL - England TA - J Physiol JT - The Journal of physiology JID - 0266262 RN - 0 (Hif1a protein, mouse) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Reactive Oxygen Species) RN - X4W3ENH1CV (Norepinephrine) SB - IM MH - Action Potentials MH - Animals MH - Blood Pressure MH - *Cardiovascular Physiological Phenomena MH - Carotid Body/*physiopathology MH - Cerebral Cortex/metabolism MH - Hypoxia/blood/metabolism/*physiopathology MH - Hypoxia-Inducible Factor 1, alpha Subunit/*deficiency/genetics/metabolism MH - Male MH - Mice MH - Mice, Transgenic MH - Neural Conduction MH - Neuronal Plasticity MH - Norepinephrine/blood MH - Phrenic Nerve/physiopathology MH - Pulmonary Ventilation MH - Reactive Oxygen Species/*metabolism MH - *Reflex MH - *Respiratory Physiological Phenomena MH - Time Factors PMC - PMC1890436 EDAT- 2006/09/16 09:00 MHDA- 2007/01/27 09:00 PMCR- 2007/12/01 CRDT- 2006/09/16 09:00 PHST- 2006/09/16 09:00 [pubmed] PHST- 2007/01/27 09:00 [medline] PHST- 2006/09/16 09:00 [entrez] PHST- 2007/12/01 00:00 [pmc-release] AID - jphysiol.2006.114033 [pii] AID - 10.1113/jphysiol.2006.114033 [doi] PST - ppublish SO - J Physiol. 2006 Dec 1;577(Pt 2):705-16. doi: 10.1113/jphysiol.2006.114033. Epub 2006 Sep 14.