title: Partial HIF-1alpha deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia.
abstract: Chronic hypoxia depolarizes and reduces K+ current in pulmonary arterial smooth muscle cells (PASMCs). Our laboratory previously demonstrated that hypoxia-inducible factor-1 (HIF-1) contributed to the development of hypoxic pulmonary hypertension. In this study, electrophysiological parameters were measured in PASMCs isolated from intrapulmonary arteries of mice with one null allele at the Hif1a locus encoding HIF-1alpha [Hif1a(+/-)] and from their wild-type [Hif1a(+/+)] littermates after 3 wk in air or 10% O2. Hematocrit and right ventricular wall and left ventricle plus septum weights were measured. Capacitance, K+ current, and membrane potential were measured with whole cell patch clamp. Similar to our laboratory's previous results, hypoxia-induced right ventricular hypertrophy and polycythemia were blunted in Hif1a(+/-) mice. Hypoxia increased PASMC capacitance in Hif1a(+/+) mice but not in Hif1a(+/-) mice. Chronic hypoxia depolarized and reduced K+ current density in PASMCs from Hif1a(+/+) mice. In PASMCs from hypoxic Hif1a(+/-) mice, no reduction in K+ current density was observed, and depolarization was significantly blunted. Thus partial deficiency of HIF-1alpha is sufficient to impair hypoxia-induced depolarization, reduction of K+ current density, and PASMC hypertrophy.
authors.affiliation: Division of Pulmonary and Critical Care Medicine and Institute of Genetic Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21224, USA. shimodal@wech.jhu.edu
authors.forename: L A
authors.initials: LA
authors.lastname: Shimoda
authors.forename: D J
authors.initials: DJ
authors.lastname: Manalo
authors.forename: J S
authors.initials: JS
authors.lastname: Sham
authors.forename: G L
authors.initials: GL
authors.lastname: Semenza
authors.forename: J T
authors.initials: JT
authors.lastname: Sylvester
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004553:Electric Conductivity; D004594:Electrophysiology; D006400:Hematocrit; D017380:Hypertrophy, Right Ventricular / Q000209:etiology; D000860:Hypoxia / Q000097:blood / Q000150:complications / Q000503:physiopathology*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology*; D012016:Reference Values; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D015221:Potassium Channels; D014157:Transcription Factors