title: Regulation of hypoxia-inducible factor-α isoforms and redox state by carotid body neural activity in rats.
abstract: Previous studies reported that chronic intermittent hypoxia (CIH) results in an imbalanced expression of hypoxia-inducible factor-α (HIF-α) isoforms and oxidative stress in rodents, which may be due either to the direct effect of CIH or indirectly via hitherto uncharacterized mechanism(s). As neural activity is a potent regulator of gene transcription, we hypothesized that carotid body (CB) neural activity contributes to CIH-induced HIF-α isoform expression and oxidative stress in the chemoreflex pathway. Experiments were performed on adult rats exposed to CIH for 10 days. Rats exposed to CIH exhibited: increased HIF-1α and decreased HIF-2α expression; increased NADPH oxidase 2 and decreased superoxide dismutase 2 expression; and oxidative stress in the nucleus tractus solitarius and rostral ventrolateral medulla as well as in the adrenal medulla (AM), a major end organ of the sympathetic nervous system. Selective ablation of the CB abolished these effects. In the AM, sympathetic activation by the CB chemoreflex mediates CIH-induced HIF-α isoform imbalance via muscarinic acetylcholine receptor-mediated Ca(2+) influx, and the resultant activation of mammalian target of rapamycin pathway and calpain proteases. Rats exposed to CIH presented with hypertension, elevated sympathetic activity and increased circulating catecholamines. Selective ablation of either the CB (afferent pathway) or sympathetic innervation to the AM (efferent pathway) abolished these effects. These observations uncover CB neural activity-dependent regulation of HIF-α isoforms and the redox state by CIH in the central and peripheral nervous systems associated with the chemoreflex.
authors: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, IL, 60637, USA.
authors: Ying-Jie
authors: YJ
authors: Peng
authors: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, IL, 60637, USA.
authors: Guoxiang
authors: G
authors: Yuan
authors: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, IL, 60637, USA.
authors: Shakil
authors: S
authors: Khan
authors: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, IL, 60637, USA.
authors: Jayasri
authors: J
authors: Nanduri
authors: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, IL, 60637, USA.
authors: Vladislav V
authors: VV
authors: Makarenko
authors: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, IL, 60637, USA.
authors: Vaddi Damodara
authors: VD
authors: Reddy
authors: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, IL, 60637, USA.
authors: Chirag
authors: C
authors: Vasavda
authors: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, IL, 60637, USA.
authors: Ganesh K
authors: GK
authors: Kumar
authors: Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, Radiation Oncology and Biological Chemistry, and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors: Gregg L
authors: GL
authors: Semenza
authors: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, IL, 60637, USA nanduri@uchicago.edu.
authors: Nanduri R
authors: NR
authors: Prabhakar
mesh_terms: D000313:Adrenal Medulla / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D002344:Carotid Body / Q000502:physiology*; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex; D017552:Solitary Nucleus / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002118:Calcium; D002154:Calpain; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019255:NADPH Oxidases; D020033:Protein Isoforms; D013482:Superoxide Dismutase; D058570:TOR Serine-Threonine Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C497444:Hif1a protein, rat