IGF-1 signaling in neonatal hypoxia-induced pulmonary hypertension: Role of epigenetic regulation

Qiwei Yang, Miranda Sun, Ramaswamy Ramchandran, J. Usha Raj

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Pulmonary hypertension is a fatal disease characterized by a progressive increase in pulmonary artery pressure accompanied by pulmonary vascular remodeling and increased vasomotor tone. Although some biological pathways have been identified in neonatal hypoxia-induced pulmonary hypertension (PH), little is known regarding the role of growth factors in the pathogenesis of PH in neonates. In this study, using a model of hypoxia-induced PH in neonatal mice, we demonstrate that the growth factor insulin-like growth factor-1 (IGF-1), a potent activator of the AKT signaling pathway, is involved in neonatal PH. After exposure to hypoxia, IGF-1 signaling is activated in pulmonary endothelial and smooth muscle cells in vitro, and the IGF-1 downstream signal pAKTS473 is upregulated in lungs of neonatal mice. We found that IGF-1 regulates ET-1 expression in pulmonary endothelial cells and that IGF-1 expression is regulated by histone deacetylases (HDACs). In addition, there is a differential cytosine methylation site in the IGF-1 promoter region in response to neonatal hypoxia. Moreover, inhibition of HDACs with apicidin decreases neonatal hypoxia-induced global DNA methylation levels in lungs and specific cytosine methylation levels around the pulmonary IGF-1 promoter region. Finally, HDAC inhibition with apicidin reduces chronic hypoxia-induced activation of IGF-1/pAKT signaling in lungs and attenuates right ventricular hypertrophy and pulmonary vascular remodeling. Taken together, we conclude that IGF-1, which is epigenetically regulated, is involved in the pathogenesis of pulmonary hypertension in neonatal mice. This study implicates a novel HDAC/IGF-1 epigenetic pathway in the regulation of hypoxia-induced PH and warrants further study of the role of IGF-1 in neonatal pulmonary hypertensive disease.

Original languageEnglish (US)
Pages (from-to)20-31
Number of pages12
JournalVascular Pharmacology
Volume73
DOIs
Publication statusPublished - Oct 1 2015

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Keywords

  • DNA methylation
  • Endothelin-1
  • Histone deacetylase
  • IGF-1
  • Neonatal hypoxia
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

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