title: An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension.
abstract: BACKGROUND
  The cause of pulmonary arterial hypertension (PAH) was investigated in humans and fawn hooded rats (FHR), a spontaneously pulmonary hypertensive strain.
  
  
  RESULTS
  Serial Doppler echocardiograms and cardiac catheterizations were performed in FHR and FHR/BN1, a consomic control that is genetically identical except for introgression of chromosome 1. PAH began after 20 weeks of age, causing death by &60 weeks. FHR/BN1 did not develop PAH. FHR pulmonary arterial smooth muscle cells (PASMCs) had a rarified reticulum of hyperpolarized mitochondria with reduced expression of electron transport chain components and superoxide dismutase-2. These mitochondrial abnormalities preceded PAH and persisted in culture. Depressed mitochondrial reactive oxygen species (ROS) production caused normoxic activation of hypoxia inducible factor (HIF-1alpha), which then inhibited expression of oxygen-sensitive, voltage-gated K+ channels (eg, Kv1.5). Disruption of this mitochondrial-HIF-Kv pathway impaired oxygen sensing (reducing hypoxic pulmonary vasoconstriction, causing polycythemia), analogous to the pathophysiology of chronically hypoxic Sprague-Dawley rats. Restoring ROS (exogenous H2O2) or blocking HIF-1alpha activation (dominant-negative HIF-1alpha) restored Kv1.5 expression/function. Dichloroacetate, a mitochondrial pyruvate dehydrogenase kinase inhibitor, corrected the mitochondrial-HIF-Kv pathway in FHR-PAH and human PAH PASMCs. Oral dichloroacetate regressed FHR-PAH and polycythemia, increasing survival. Chromosome 1 genes that were dysregulated in FHRs and relevant to the mitochondria-HIF-Kv pathway included HIF-3alpha (an HIF-1alpha repressor), mitochondrial cytochrome c oxidase, and superoxide dismutase-2. Like FHRs, human PAH-PASMCs had dysmorphic, hyperpolarized mitochondria; normoxic HIF-1alpha activation; and reduced expression/activity of HIF-3alpha, cytochrome c oxidase, and superoxide dismutase-2.
  
  
  CONCLUSIONS
  FHRs have a chromosome 1 abnormality that disrupts a mitochondria-ROS-HIF-Kv pathway, leading to PAH. Similar abnormalities occur in idiopathic human PAH. This study reveals an intersection between oxygen-sensing mechanisms and PAH. The mitochondria-ROS-HIF-Kv pathway offers new targets for PAH therapy.
authors.affiliation: Vascular Biology Group, Division of Cardiology, University of Alberta, Edmonton, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Porter
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Andrade-Navarro
authors.forename: Bernard
authors.initials: B
authors.lastname: Thébaud
authors.forename: Sandra
authors.initials: S
authors.lastname: Bonnet
authors.forename: Alois
authors.initials: A
authors.lastname: Haromy
authors.forename: Gwyneth
authors.initials: G
authors.lastname: Harry
authors.forename: Rohit
authors.initials: R
authors.lastname: Moudgil
authors.forename: M Sean
authors.initials: MS
authors.lastname: McMurtry
authors.forename: E Kenneth
authors.initials: EK
authors.lastname: Weir
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D000818:Animals; D006328:Cardiac Catheterization; D002869:Chromosome Aberrations; D002878:Chromosomes, Human, Pair 1; D003999:Dichloroacetic Acid / Q000494:pharmacology; D015150:Echocardiography, Doppler; D003576:Electron Transport Complex IV / Q000032:analysis / Q000235:genetics; D005786:Gene Expression Regulation; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000503:physiopathology*; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D008297:Male; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000201:enzymology / Q000648:ultrastructure; D010100:Oxygen / Q000502:physiology*; D015221:Potassium Channels / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013482:Superoxide Dismutase / Q000032:analysis / Q000235:genetics; D014661:Vasoconstriction / Q000502:physiology; D000099156:Superoxide Dismutase 2
chemical_list: D003999:Dichloroacetic Acid; D003576:Electron Transport Complex IV; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D015221:Potassium Channels; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C497444:Hif1a protein, rat