{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T22:15:27Z","timestamp":1773872127693,"version":"3.50.1"},"reference-count":54,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2018,1,4]],"date-time":"2018-01-04T00:00:00Z","timestamp":1515024000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["PO1\u2010HL\u201090554"],"award-info":[{"award-number":["PO1\u2010HL\u201090554"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>The mechanisms underlying long\u2010term (30\u00a0days) intermittent hypoxia (LT\u2010IH)\u2010evoked DNA methylation of anti\u2010oxidant enzyme (AOE) gene repression in the carotid body (CB) reflex pathway were examined.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>LT\u2010IH\u2010treated rats showed increased reactive oxygen species (ROS) levels in the CB reflex pathway.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Administration of a ROS scavenger or CB ablation blocked LT\u2010IH\u2010evoked DNA methylation and AOE gene repression in the central and efferent limbs of the CB reflex.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>LT\u2010IH increased DNA methyltransferase (Dnmt) activity through upregulation of Dnmt1 and 3b proteins by ROS\u2010dependent inactivation of glycogen synthase kinase 3\u03b2 (GSK3\u03b2) by Akt.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>A pan\u2010Akt inhibitor prevented LT\u2010IH\u2010induced GSK3\u03b2 inactivation, elevated Dnmt protein expression and activity, AOE gene methylation, sympathetic activation and hypertension.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Long\u2010term exposure to intermittent hypoxia (LT\u2010IH; 30\u00a0days), simulating blood O<jats:sub>2<\/jats:sub> profiles during sleep apnoea, has been shown to repress anti\u2010oxidant enzyme (AOE) gene expression by DNA methylation in the carotid body (CB) reflex pathway, resulting in persistent elevation of plasma catecholamine levels and blood pressure. The present study examined the mechanisms by which LT\u2010IH induces DNA methylation. Adult rats exposed to LT\u2010IH showed elevated reactive oxygen species (ROS) in the CB, nucleus tractus solitarius (nTS) and rostroventrolateral medulla (RVLM) and adrenal medulla (AM), which represent the central and efferent limbs of the CB reflex, respectively. ROS scavenger treatment during the first ten days of IH exposure prevented ROS accumulation, blocked DNA methylation, and normalized AOE gene expression, suggesting that ROS generated during the early stages of IH activate DNA methylation. CB ablation prevented the ROS accumulation, normalized AOE gene expression in the nTS, RVLM, and AM and blocked DNA methylation, suggesting that LT\u2010IH\u2010induced DNA methylation in the central and efferent limbs of the CB reflex is indirect and requires CB neural activity. LT\u2010IH increased DNA methyl transferase (Dnmt) activity through upregulation of Dnmt1 and 3b protein expression due to ROS\u2010dependent inactivation of glycogen synthase kinase 3\u03b2 (GSK3\u03b2) by protein kinase B (Akt). Treating rats with the pan\u2010Akt inhibitor GSK690693 blocked the induction of Dnmt activity, Dnmt protein expression, and DNA methylation, leading to normalization of AOE gene expression as well as plasma catecholamine levels and blood pressure.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp274833","type":"journal-article","created":{"date-parts":[[2017,11,17]],"date-time":"2017-11-17T09:52:57Z","timestamp":1510912377000},"page":"3087-3100","source":"Crossref","is-referenced-by-count":20,"title":["DNA methylation in the central and efferent limbs of the chemoreflex requires carotid body neural activity"],"prefix":"10.1113","volume":"596","author":[{"given":"Jayasri","family":"Nanduri","sequence":"first","affiliation":[{"name":"Institute for Integrative Physiology and Centre for Systems Biology of O<sub>2<\/sub> Sensing, Biological Science Division The University of Chicago  Chicago IL 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