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

21 Citations (Scopus)

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
StatePublished - Oct 1 2015

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Somatomedins
Pulmonary Hypertension
Epigenomics
Lung
Histone Deacetylases
Cytosine
Genetic Promoter Regions
Methylation
Intercellular Signaling Peptides and Proteins
Hypoxia
Right Ventricular Hypertrophy
DNA Methylation
Pulmonary Artery
Lung Diseases
Smooth Muscle Myocytes
Endothelial Cells
Pressure

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

Cite this

IGF-1 signaling in neonatal hypoxia-induced pulmonary hypertension : Role of epigenetic regulation. / Yang, Qiwei; Sun, Miranda; Ramchandran, Ramaswamy; Raj, J. Usha.

In: Vascular Pharmacology, Vol. 73, 01.10.2015, p. 20-31.

Research output: Contribution to journalArticle

Yang, Qiwei ; Sun, Miranda ; Ramchandran, Ramaswamy ; Raj, J. Usha. / IGF-1 signaling in neonatal hypoxia-induced pulmonary hypertension : Role of epigenetic regulation. In: Vascular Pharmacology. 2015 ; Vol. 73. pp. 20-31.
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