title: Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation and apoptosis resistance in pulmonary artery smooth muscle cells (PASMCs).
  
  
  OBJECTIVE
  We reasoned that chloroquine, based on its ability to inhibit autophagy and block lysosomal degradation of the bone morphogenetic protein type II receptor (BMPR-II), might exert beneficial effects in this disease.
  
  
  RESULTS
  PAH was induced in male Sprague-Dawley rats by administering monocrotaline. The induction of PAH was associated with changes in lung expression of LC3B-II, ATG5, and p62, consistent with increased autophagy, and decreased BMPR-II protein expression. Administration of chloroquine prevented the development of PAH, right ventricular hypertrophy, and vascular remodelling after monocrotaline, and prevented progression of established PAH in this model. Similar results were obtained with hydroxychloroquine. Chloroquine treatment increased whole lung and PASMC p62 protein levels consistent with inhibition of autophagy, and increased levels of BMPR-II protein. Chloroquine inhibited proliferation and increased apoptosis of PASMCs in vivo. In cultured rat PASMCs we confirmed that chloroquine both inhibited autophagy pathways and increased expression of BMPR-II protein via lysosomal inhibition. Consistent with the in vivo findings, chloroquine inhibited the proliferation and stimulated apoptosis of rat PASMCs in vitro, with no effect on endothelial cell proliferation or survival. Moreover, direct inhibition of autophagy pathways by ATG5 small interfering RNA knockdown inhibited proliferation of rat PASMCs.
  
  
  CONCLUSIONS
  Chloroquine and hydroxychloroquine exert beneficial effects in experimental PAH. The mechanism of action includes inhibition of autophagy pathways and inhibition of lysosomal degradation of BMPR-II.
authors: Department of Medicine, Division of Respiratory Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
authors: Lu
authors: L
authors: Long
authors: Xudong
authors: X
authors: Yang
authors: Mark
authors: M
authors: Southwood
authors: Junyu
authors: J
authors: Lu
authors: Stefan J
authors: SJ
authors: Marciniak
authors: Benjamin J
authors: BJ
authors: Dunmore
authors: Nicholas W
authors: NW
authors: Morrell
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D002738:Chloroquine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018450:Disease Progression; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D002738:Chloroquine; C498220:Bmpr2 protein, rat; D052006:Bone Morphogenetic Protein Receptors, Type II