PMID- 27506145 OWN - NLM STAT- MEDLINE DCOM- 20170925 LR - 20200204 IS - 1469-7793 (Electronic) IS - 0022-3751 (Print) IS - 0022-3751 (Linking) VI - 595 IP - 1 DP - 2017 Jan 1 TI - Epigenetic regulation of redox state mediates persistent cardiorespiratory abnormalities after long-term intermittent hypoxia. PG - 63-77 LID - 10.1113/JP272346 [doi] AB - KEY POINTS: The effects of short-term (ST; 10 days) and long-term (LT; 30 days) intermittent hypoxia (IH) on blood pressure (BP), breathing and carotid body (CB) chemosensory reflex were examined in adult rats. ST- and LT-IH treated rats exhibited hypertension, irregular breathing with apnoea and augmented the CB chemosensory reflex, with all these responses becoming normalized during recovery from ST- but not from LT-IH. The persistent cardiorespiratory responses to LT-IH were associated with elevated reactive oxygen species (ROS) levels in the CB and adrenal medulla, which were a result of DNA methylation-dependent suppression of genes encoding anti-oxidant enzymes (AOEs). Treating rats with decitabine either during LT-IH or during recovery from LT-IH prevented DNA methylation of AOE genes, normalized the expression of AOE genes and ROS levels, reversed the heightened CB chemosensory reflex and hypertension, and also stabilized breathing. ABSTRACT: Rodents exposed to chronic intermittent hypoxia (IH), simulating blood O(2) saturation profiles during obstructive sleep apnoea (OSA), have been shown to exhibit a heightened carotid body (CB) chemosensory reflex and hypertension. CB chemosensory reflex activation also results in unstable breathing with apnoeas. However, the effect of chronic IH on breathing is not known. In the present study, we examined the effects of chronic IH on breathing along with blood pressure (BP) and assessed whether the autonomic responses are normalized after recovery from chronic IH. Studies were performed on adult, male, Sprague-Dawley rats exposed to either short-term (ST; 10 days) or long-term (LT, 30 days) IH. Rats exposed to either ST- or LT-IH exhibited hypertension, irregular breathing with apnoeas, an augmented CB chemosensory reflex as indicated by elevated CB neural activity and plasma catecholamine levels, and elevated reactive oxygen species (ROS) levels in the CB and adrenal medulla (AM). All these effects were normalized after recovery from ST-IH but not from LT-IH. Analysis of the molecular mechanisms underlying the persistent effects of LT-IH revealed increased DNA methylation of genes encoding anti-oxidant enzymes (AOEs). Treatment with decitabine, a DNA methylation inhibitor, either during LT-IH or during recovery from LT-IH, prevented DNA methylation, normalized the expression of AOE genes, ROS levels, CB chemosensory reflex and BP, and also stabilized breathing. These results suggest that persistent cardiorespiratory abnormalities caused by LT-IH are mediated by epigenetic re-programming of the redox state in the CB chemosensory reflex pathway. CI - (c) 2016 The Authors. The Journal of Physiology (c) 2016 The Physiological Society. FAU - Nanduri, Jayasri AU - Nanduri J AD - Institute For Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Science Division, The University of Chicago, Chicago, IL, USA. FAU - Peng, Ying-Jie AU - Peng YJ AD - Institute For Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Science Division, The University of Chicago, Chicago, IL, USA. FAU - Wang, Ning AU - Wang N AD - Institute For Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Science Division, The University of Chicago, Chicago, IL, USA. FAU - Khan, Shakil A AU - Khan SA AD - Institute For Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Science Division, The University of Chicago, Chicago, IL, USA. FAU - Semenza, Gregg L AU - Semenza GL AD - Vascular Program, Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, Radiation Oncology and Biological Chemistry, and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. FAU - Kumar, Ganesh K AU - Kumar GK AD - Institute For Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Science Division, The University of Chicago, Chicago, IL, USA. FAU - Prabhakar, Nanduri R AU - Prabhakar NR AD - Institute For Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Science Division, The University of Chicago, Chicago, IL, USA. LA - eng GR - P01 HL090554/HL/NHLBI NIH HHS/United States GR - UH2 HL123610/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20161002 PL - England TA - J Physiol JT - The Journal of physiology JID - 0266262 RN - 0 (Reactive Oxygen Species) RN - 4Y8F71G49Q (Malondialdehyde) RN - EC 1.11.1.15 (Peroxiredoxins) RN - EC 1.11.1.15 (Prdx4 protein, rat) RN - EC 1.11.1.6 (Catalase) RN - EC 1.11.1.9 (Glutathione Peroxidase) RN - EC 1.11.1.9 (glutathione peroxidase 2, rat) RN - EC 1.15.1.1 (Sod1 protein, rat) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 1.15.1.1 (Superoxide Dismutase-1) RN - EC 1.15.1.1 (superoxide dismutase 2) RN - EC 4.2.1.3 (Aconitate Hydratase) RN - X4W3ENH1CV (Norepinephrine) SB - IM CIN - J Physiol. 2017 Feb 1;595(3):629-630. PMID: 28145012 MH - Aconitate Hydratase/metabolism MH - Adrenal Medulla/metabolism MH - Animals MH - Blood Pressure MH - Carotid Body/metabolism/physiology MH - Catalase/genetics MH - DNA Methylation MH - Epigenesis, Genetic MH - Gene Expression MH - Glutathione Peroxidase/genetics MH - Hypertension/blood/genetics/metabolism/*physiopathology MH - Hypoxia/blood/genetics/metabolism/*physiopathology MH - Male MH - Malondialdehyde/metabolism MH - Norepinephrine/blood MH - Oxidation-Reduction MH - Peroxiredoxins/genetics MH - Rats, Sprague-Dawley MH - Reactive Oxygen Species/metabolism MH - Respiration Disorders/blood/genetics/metabolism/*physiopathology MH - Superoxide Dismutase/genetics/metabolism MH - Superoxide Dismutase-1/genetics PMC - PMC5199741 OTO - NOTNLM OT - adrenal medulla OT - anti-oxidant enzymes OT - blood pressures OT - carotid body OT - catecholamine OT - epigenetic changes EDAT- 2016/08/11 06:00 MHDA- 2017/09/26 06:00 PMCR- 2018/01/01 CRDT- 2016/08/11 06:00 PHST- 2016/02/25 00:00 [received] PHST- 2016/07/25 00:00 [accepted] PHST- 2016/08/11 06:00 [pubmed] PHST- 2017/09/26 06:00 [medline] PHST- 2016/08/11 06:00 [entrez] PHST- 2018/01/01 00:00 [pmc-release] AID - TJP7458 [pii] AID - 10.1113/JP272346 [doi] PST - ppublish SO - J Physiol. 2017 Jan 1;595(1):63-77. doi: 10.1113/JP272346. Epub 2016 Oct 2.