title: Enhanced neuropeptide Y synthesis during intermittent hypoxia in the rat adrenal medulla: role of reactive oxygen species-dependent alterations in precursor peptide processing.
abstract: Intermittent hypoxia (IH) associated with recurrent apneas often leads to cardiovascular abnormalities. Previously, we showed that IH treatment elevates blood pressure and increases plasma catecholamines (CAs) in rats via reactive oxygen species (ROS)-dependent enhanced synthesis and secretion from the adrenal medulla (AM). Neuropeptide Y (NPY), a sympathetic neurotransmitter that colocalizes with CA in the AM, has been implicated in blood pressure regulation during persistent stress. Here, we investigated whether IH facilitates NPY synthesis in the rat AM and assessed the role of ROS signaling. IH increased NPY-like immunoreactivity in many dopamine-β-hydroxylase-expressing chromaffin cells with a parallel increase in preproNPY mRNA and protein. IH increased the activities of proNPY-processing enzymes, which were due, in part, to elevated protein expression and increased proteolytic processing. IH increased ROS generation, and antioxidants reversed IH-induced increases in ROS, preproNPY, and its processing to bioactive NPY in the AM. IH treatment increased blood pressure and antioxidants and inhibition of NPY amidation prevented this response. These findings suggest that IH-induced elevation in NPY expression in the rat AM is mediated by ROS-dependent augmentation of preproNPY mRNA expression and proNPY-processing enzyme activities and contributes to IH-induced elevation of blood pressure.
authors.affiliation: The Center for Systems Biology of O2 Sensing, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Gayatri
authors.initials: G
authors.lastname: Raghuraman
authors.forename: Apeksha
authors.initials: A
authors.lastname: Kalari
authors.forename: Rishi
authors.initials: R
authors.lastname: Dhingra
authors.forename: Nanduri R
authors.initials: NR
authors.lastname: Prabhakar
authors.forename: Ganesh K
authors.initials: GK
authors.lastname: Kumar
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000302:Adrenal Cortex / Q000378:metabolism; D000313:Adrenal Medulla / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D043423:Carboxypeptidase H / Q000378:metabolism; D056668:Cathepsin L / Q000378:metabolism; D015687:Cell Hypoxia; D019439:Chromaffin Cells / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D045664:Proprotein Convertase 1 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017783:Superior Cervical Ganglion / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D005229:Fatty Acids, Monounsaturated; D008665:Metalloporphyrins; C502230:Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin; D009097:Multienzyme Complexes; D009478:Neuropeptide Y; D017382:Reactive Oxygen Species; C064180:4-phenyl-3-butenoic acid; D006899:Mixed Function Oxygenases; D004299:Dopamine beta-Hydroxylase; C035189:peptidylglycine monooxygenase; D043423:Carboxypeptidase H; D045664:Proprotein Convertase 1; D056668:Cathepsin L; C534280:Ctsl protein, rat; D000111:Acetylcysteine