title: Autophagic protein LC3B confers resistance against hypoxia-induced pulmonary hypertension.
abstract: BACKGROUND
  Pulmonary hypertension (PH) is a progressive disease with unclear etiology. The significance of autophagy in PH remains unknown.
  
  
  OBJECTIVE
  To determine the mechanisms by which autophagic proteins regulate tissue responses during PH.
  
  
  METHODS
  Lungs from patients with PH, lungs from mice exposed to chronic hypoxia, and human pulmonary vascular cells were examined for autophagy using electron microscopy and Western analysis. Mice deficient in microtubule-associated protein-1 light chain-3B (LC3B(-/-)), or early growth response-1 (Egr-1(-/-)), were evaluated for vascular morphology and hemodynamics.
  
  
  RESULTS
  Human PH lungs displayed elevated lipid-conjugated LC3B, and autophagosomes relative to normal lungs. These autophagic markers increased in hypoxic mice, and in human pulmonary vascular cells exposed to hypoxia. Egr-1, which regulates LC3B expression, was elevated in PH, and increased by hypoxia in vivo and in vitro. LC3B(-/-) or Egr-1(-/-), but not Beclin 1(+/-), mice displayed exaggerated PH during hypoxia. In vitro, LC3B knockdown increased reactive oxygen species production, hypoxia-inducible factor-1α stabilization, and hypoxic cell proliferation. LC3B and Egr-1 localized to caveolae, associated with caveolin-1, and trafficked to the cytosol during hypoxia.
  
  
  CONCLUSIONS
  The results demonstrate elevated LC3B in the lungs of humans with PH, and of mice with hypoxic PH. The increased susceptibility of LC3B(-/-) and Egr-1(-/-) mice to hypoxia-induced PH and increased hypoxic proliferation of LC3B knockdown cells suggest adaptive functions of these proteins during hypoxic vascular remodeling. The results suggest that autophagic protein LC3B exerts a protective function during the pathogenesis of PH, through the regulation of hypoxic cell proliferation.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Seon-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Akaya
authors.initials: A
authors.lastname: Smith
authors.forename: Lanping
authors.initials: L
authors.lastname: Guo
authors.forename: Tero-Pekka
authors.initials: TP
authors.lastname: Alastalo
authors.forename: Molong
authors.initials: M
authors.lastname: Li
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawada
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Chen
authors.forename: Emeka
authors.initials: E
authors.lastname: Ifedigbo
authors.forename: Yang
authors.initials: Y
authors.lastname: Jin
authors.forename: Carol
authors.initials: C
authors.lastname: Feghali-Bostwick
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Hong Pyo
authors.initials: HP
authors.lastname: Kim
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D000328:Adult; D000818:Animals; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D015687:Cell Hypoxia; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D015415:Biomarkers; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C477012:MAP1LC3A protein, human; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species