title: Mechanism of the susceptibility of remodeled pulmonary vessels to drug-induced cell killing.
abstract: BACKGROUND
  Pulmonary arterial hypertension remains a devastating disease without a cure. The major complication of this disease is the abnormal growth of vascular cells, resulting in pulmonary vascular remodeling. Thus, agents, which affect the remodeled vessels by killing unwanted cells, should improve treatment strategies. The present study reports that antitumor drugs selectively kill vascular cells in remodeled pulmonary vessels in rat models of pulmonary hypertension.
  
  
  RESULTS
  After developing pulmonary vascular remodeling in chronic hypoxia or chronic hypoxia/SU-5416 models, rats were injected with antitumor drugs including proteasome inhibitors (bortezomib and MG-132) and daunorubicin. Within 1 to 3 days, these agents reduced the media and intima thickness of remodeled pulmonary vascular walls, but not the thickness of normal pulmonary vessels. These drugs also promoted apoptotic and autophagic death of vascular cells in the remodeled vessels, but not in normal vessels. We provide evidence that the upregulation of annexin A1, leading to GATA4-dependent downregulation of Bcl-xL, is a mechanism for specific apoptotic killing, and for the role of parkin in defining specificity of autophagic killing of remodeled vascular cells. The reversal of pulmonary vascular remodeling increased the capacity of vasodilators to reduce pulmonary arterial pressure.
  
  
  CONCLUSIONS
  These results suggest that antitumor drugs can specifically kill cells in remodeled pulmonary vascular walls and may be useful for improving the efficacy of current therapeutic strategies to treat pulmonary arterial hypertension.
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, 20057, DC.
authors.forename: Yasmine F
authors.initials: YF
authors.lastname: Ibrahim
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Wong
authors.forename: Ludmila
authors.initials: L
authors.lastname: Pavlickova
authors.forename: Lingling
authors.initials: L
authors.lastname: Liu
authors.forename: Lobsang
authors.initials: L
authors.lastname: Trasar
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Bansal
authors.forename: Yuichiro J
authors.initials: YJ
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D062186:Arterial Pressure / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension; D050991:GATA4 Transcription Factor / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications; D008297:Male; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases; D014665:Vasodilator Agents / Q000494:pharmacology; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D017305:Annexin A1; D000970:Antineoplastic Agents; C494813:Bcl2l1 protein, rat; D050991:GATA4 Transcription Factor; C084365:Gata4 protein, rat; D014665:Vasodilator Agents; D051020:bcl-X Protein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: apoptosis; autophagy; blood pressure; pulmonary hypertension; vascular remodeling