title: Epigenetic regulation of redox state mediates persistent cardiorespiratory abnormalities after long-term intermittent hypoxia.
abstract: 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.
  
  
  
  Rodents exposed to chronic intermittent hypoxia (IH), simulating blood O2saturation 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.
authors: Institute For Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Science Division, The University of Chicago, Chicago, IL, USA.
authors: Jayasri
authors: J
authors: Nanduri
authors: Institute For Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Science Division, The University of Chicago, Chicago, IL, USA.
authors: Ying-Jie
authors: YJ
authors: Peng
authors: Institute For Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Science Division, The University of Chicago, Chicago, IL, USA.
authors: Ning
authors: N
authors: Wang
authors: Institute For Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Science Division, The University of Chicago, Chicago, IL, USA.
authors: Shakil A
authors: SA
authors: Khan
authors: 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.
authors: Gregg L
authors: GL
authors: Semenza
authors: Institute For Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Science Division, The University of Chicago, Chicago, IL, USA.
authors: Ganesh K
authors: GK
authors: Kumar
authors: Institute For Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Science Division, The University of Chicago, Chicago, IL, USA.
authors: Nanduri R
authors: NR
authors: Prabhakar
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000313:Adrenal Medulla / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D002344:Carotid Body / Q000378:metabolism / Q000502:physiology; D002374:Catalase / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000235:genetics; D006973:Hypertension / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000860:Hypoxia / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood; D010084:Oxidation-Reduction; D054464:Peroxiredoxins / Q000235:genetics; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012120:Respiration Disorders / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000235:genetics; D000099156:Superoxide Dismutase 2
chemical_list: D000154:Aconitate Hydratase; D002374:Catalase; D005979:Glutathione Peroxidase; D008315:Malondialdehyde; D009638:Norepinephrine; D054464:Peroxiredoxins; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2; C515982:Prdx4 protein, rat; C525844:glutathione peroxidase 2, rat; C000606292:Sod1 protein, rat
keywords: adrenal medulla; anti-oxidant enzymes; blood pressures; carotid body; catecholamine; epigenetic changes