title: Chronic hypoxia limits H2O2-induced inhibition of ASIC1-dependent store-operated calcium entry in pulmonary arterial smooth muscle.
abstract: Our laboratory shows that acid-sensing ion channel 1 (ASIC1) contributes to the development of hypoxic pulmonary hypertension by augmenting store-operated Ca(2+) entry (SOCE) that is associated with enhanced agonist-induced vasoconstriction and arterial remodeling. However, this enhanced Ca(2+) influx following chronic hypoxia (CH) is not dependent on an increased ASIC1 protein expression in pulmonary arterial smooth muscle cells (PASMC). It is well documented that hypoxic pulmonary hypertension is associated with changes in redox potential and reactive oxygen species homeostasis. ASIC1 is a redox-sensitive channel showing increased activity in response to reducing agents, representing an alternative mechanism of regulation. We hypothesize that the enhanced SOCE following CH results from removal of an inhibitory effect of hydrogen peroxide (H2O2) on ASIC1. We found that CH increased PASMC superoxide (O2 (·-)) and decreased rat pulmonary arterial H2O2 levels. This decrease in H2O2 is a result of decreased Cu/Zn superoxide dismutase expression and activity, as well as increased glutathione peroxidase (GPx) expression and activity following CH. Whereas H2O2 inhibited ASIC1-dependent SOCE in PASMC from control and CH animals, addition of catalase augmented ASIC1-mediated SOCE in PASMC from control rats but had no further effect in PASMC from CH rats. These data suggest that, under control conditions, H2O2 inhibits ASIC1-dependent SOCE. Furthermore, H2O2 levels are decreased following CH as a result of diminished dismutation of O2 (·-) and increased H2O2 catalysis through GPx-1, leading to augmented ASIC1-dependent SOCE.
authors.affiliation: Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Plomaritas
authors.affiliation: Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Herbert
authors.affiliation: Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
authors.forename: Tracylyn R
authors.initials: TR
authors.lastname: Yellowhair
authors.affiliation: Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Resta
authors.affiliation: Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
authors.forename: Laura V
authors.initials: LV
authors.lastname: Gonzalez Bosc
authors.affiliation: Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
authors.forename: Benjimen R
authors.initials: BR
authors.lastname: Walker
authors.affiliation: Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico NJernigan@salud.unm.edu.
authors.forename: Nikki L
authors.initials: NL
authors.lastname: Jernigan
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002478:Cells, Cultured; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D000860:Hypoxia; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000502:physiology; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2
chemical_list: D062565:Acid Sensing Ion Channels; D002118:Calcium; D015220:Calcium Channels; D006861:Hydrogen Peroxide; D016877:Oxidants; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2; C568268:Asic1 protein, rat; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat
keywords: catalase; degenerin/epithelial sodium channel; di-(4-carboxybenzyl) hyponitrite-1; glutathione peroxidase; pulmonary hypertension; superoxide dismutase