{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T13:14:00Z","timestamp":1789910040243,"version":"4.0.1"},"reference-count":53,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2014,7,28]],"date-time":"2014-07-28T00:00:00Z","timestamp":1406505600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"National Institutes of Health, Heart, Lung and Blood Institute","award":["PO1-HL-90554"],"award-info":[{"award-number":["PO1-HL-90554"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2014,9]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\"><jats:list-item><jats:p>Rats exposed to chronic intermittent hypoxia (CIH) exhibited imbalanced expression of hypoxia\u2010inducible factor (HIF)\u2010\u03b1 isoforms and oxidative stress in brainstem regions associated with the carotid body (CB) chemoreflex, and in the adrenal medulla, an end organ of the sympathetic nervous system.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Selective ablation of the CB abolished the effects of CIH on HIF\u2010\u03b1 isoform expression and oxidative stress.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>In the adrenal medulla, chemoreflex\u2010mediated sympathetic activation regulates HIF\u2010\u03b1 isoform expression via muscarinic acetylcholine receptor\u2010mediated Ca<jats:sup>2+<\/jats:sup>influx and the resultant activation of the mammalian target of rapamycin pathway and calpain proteases.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Thus, CB neural activity regulates HIF\u2010\u03b1 isoform expressions and redox state in the central and peripheral nervous system associated with the chemoreflex pathway under the setting of CIH.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Previous studies reported that chronic intermittent hypoxia (CIH) results in an imbalanced expression of hypoxia\u2010inducible factor\u2010\u03b1 (HIF\u2010\u03b1) 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\u2010induced HIF\u2010\u03b1 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\u20101\u03b1 and decreased HIF\u20102\u03b1 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\u2010induced HIF\u2010\u03b1 isoform imbalance via muscarinic acetylcholine receptor\u2010mediated Ca<jats:sup>2+<\/jats:sup>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\u2010dependent regulation of HIF\u2010\u03b1 isoforms and the redox state by CIH in the central and peripheral nervous systems associated with the chemoreflex.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jphysiol.2014.273789","type":"journal-article","created":{"date-parts":[[2014,6,28]],"date-time":"2014-06-28T04:23:04Z","timestamp":1403929384000},"page":"3841-3858","source":"Crossref","is-referenced-by-count":83,"title":["Regulation of hypoxia\u2010inducible factor\u2010\u03b1 isoforms and redox state by carotid body neural activity in rats"],"prefix":"10.1113","volume":"592","author":[{"given":"Ying\u2010Jie","family":"Peng","sequence":"first","affiliation":[{"name":"Institute for Integrative Physiology and Center for Systems Biology for O<sub>2<\/sub> Sensing Biological Sciences Division University of Chicago IL 60637 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoxiang","family":"Yuan","sequence":"additional","affiliation":[{"name":"Institute for Integrative Physiology and Center for Systems Biology for O<sub>2<\/sub> Sensing Biological Sciences Division University of Chicago IL 60637 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakil","family":"Khan","sequence":"additional","affiliation":[{"name":"Institute for Integrative Physiology and Center for Systems Biology for O<sub>2<\/sub> Sensing Biological Sciences Division University of Chicago IL 60637 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayasri","family":"Nanduri","sequence":"additional","affiliation":[{"name":"Institute for Integrative Physiology and Center for Systems Biology for O<sub>2<\/sub> Sensing Biological Sciences Division University of Chicago IL 60637 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladislav V.","family":"Makarenko","sequence":"additional","affiliation":[{"name":"Institute for Integrative Physiology and Center for Systems Biology for O<sub>2<\/sub> Sensing Biological Sciences Division University of Chicago IL 60637 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaddi Damodara","family":"Reddy","sequence":"additional","affiliation":[{"name":"Institute for Integrative Physiology and Center for Systems Biology for O<sub>2<\/sub> Sensing Biological Sciences Division University of Chicago IL 60637 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chirag","family":"Vasavda","sequence":"additional","affiliation":[{"name":"Institute for Integrative Physiology and Center for Systems Biology for O<sub>2<\/sub> Sensing Biological Sciences Division University of Chicago IL 60637 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganesh K.","family":"Kumar","sequence":"additional","affiliation":[{"name":"Institute for Integrative Physiology and Center for Systems Biology for O<sub>2<\/sub> Sensing Biological Sciences Division University of Chicago IL 60637 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregg L.","family":"Semenza","sequence":"additional","affiliation":[{"name":"Institute for Cell Engineering Departments of Pediatrics, Medicine, Oncology, Radiation Oncology and Biological Chemistry and McKusick\u2010Nathans Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore MD 21205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanduri R.","family":"Prabhakar","sequence":"additional","affiliation":[{"name":"Institute for Integrative Physiology and Center for Systems Biology for O<sub>2<\/sub> Sensing Biological Sciences Division University of Chicago IL 60637 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,7,28]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2012.237800"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2011.01258.x"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2011.00050"},{"key":"e_1_2_6_5_1","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S0031-6997(24)01362-0","article-title":"International Union of Pharmacology. 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