title: Inhibition of LRP5/6-mediated Wnt/β-catenin signaling by Mesd attenuates hyperoxia-induced pulmonary hypertension in neonatal rats.
abstract: BACKGROUND
  Hyperoxia-induced neonatal lung injury is associated with activation of Wnt/β-catenin signaling. Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are Wnt coreceptors that bind to Wnt ligands and mediate canonical Wnt/β-catenin signaling. We hypothesized that inhibition of LRP5/6 by their universal inhibitor, Mesd, would attenuate hyperoxia-induced lung injury.
  
  
  METHODS
  Newborn rat pups were randomly exposed to normoxia or hyperoxia at 90% FiO2 and injected intraperitoneally with placebo or Mesd every other day for 14 d. On day 15, phosphorylation of LRP5/6 (pLRP5/6), expression of Wnt/β-catenin target genes, cyclin D1 and Wnt-induced signaling protein-1 (WISP-1), right-ventricular systolic pressure (RVSP), right-ventricular hypertrophy (RVH), pulmonary vascular remodeling, alveolarization, and vascularization were measured.
  
  
  RESULTS
  Hyperoxia exposure markedly induced pLRP5/6, cyclin D1, and WISP-1 expression in the lungs of placebo animals, but they were significantly attenuated by the administration of Mesd. Mesd also significantly attenuated hyperoxia-induced pulmonary hypertension (PH) and pulmonary vascular remodeling. However, there was no effect on alveolarization or vascularization after Mesd administration.
  
  
  CONCLUSIONS
  This study demonstrates that LRP5/6 mediates pulmonary vascular remodeling and PH in hyperoxia-induced neonatal lung injury, thereby suggesting a potential therapeutic target to alleviate PH in neonates with severe bronchopulmonary dysplasia.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Deepthi
authors.initials: D
authors.lastname: Alapati
authors.forename: Min
authors.initials: M
authors.lastname: Rong
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Chen
authors.forename: Cuihong
authors.initials: C
authors.lastname: Lin
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Li
authors.forename: Shu
authors.initials: S
authors.lastname: Wu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D018496:Hyperoxia / Q000150:complications*; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D011247:Pregnancy; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555484:Lrp5 protein, rat; C555477:Lrp6 protein, rat; C585089:Mesd protein, rat; D018832:Molecular Chaperones; D051153:Wnt Proteins; D051176:beta Catenin