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Pediatr Res. 2013 Jun;73(6):719-25. doi: 10.1038/pr.2013.42. Epub 2013 Mar 12.

Inhibition of LRP5/6-mediated Wnt/β-catenin signaling by Mesd attenuates hyperoxia-induced pulmonary hypertension in neonatal rats.

Author information

1
Department of Pediatrics, Division of Neonatology, Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.

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.

CONCLUSION:

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.

PMID:
23481549
DOI:
10.1038/pr.2013.42
[Indexed for MEDLINE]

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