Autophagic protein LC3B confers resistance against hypoxia-induced pulmonary hypertension. Academic Article uri icon

Overview

MeSH

  • Adult
  • Animals
  • Biological Markers
  • Blotting, Western
  • Cell Hypoxia
  • Cell Proliferation
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lung
  • Male
  • Mice
  • Microscopy, Electron
  • Middle Aged
  • Reactive Oxygen Species

MeSH Major

  • Autophagy
  • Hypertension, Pulmonary
  • Microtubule-Associated Proteins

abstract

  • Pulmonary hypertension (PH) is a progressive disease with unclear etiology. The significance of autophagy in PH remains unknown. To determine the mechanisms by which autophagic proteins regulate tissue responses during PH. 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. 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. 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.

publication date

  • March 1, 2011

has subject area

  • Adult
  • Animals
  • Autophagy
  • Biological Markers
  • Blotting, Western
  • Cell Hypoxia
  • Cell Proliferation
  • Female
  • Humans
  • Hypertension, Pulmonary
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lung
  • Male
  • Mice
  • Microscopy, Electron
  • Microtubule-Associated Proteins
  • Middle Aged
  • Reactive Oxygen Species

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3081281

Digital Object Identifier (DOI)

  • 10.1164/rccm.201005-0746OC

PubMed ID

  • 20889906

Additional Document Info

start page

  • 649

end page

  • 658

volume

  • 183

number

  • 5