IGF-1 signaling in neonatal hypoxia-induced pulmonary hypertension: Role of epigenetic regulation.
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 pAKT(S473) 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.
Department of Pediatrics, University of Illinois College of Medicine, Chicago, IL, United States. Electronic address: qiwei@uic.edu.
Qiwei
Q
Yang
Department of Pediatrics, University of Illinois College of Medicine, Chicago, IL, United States.
Miranda
M
Sun
Department of Pediatrics, University of Illinois College of Medicine, Chicago, IL, United States.
Ramaswamy
R
Ramchandran
Department of Pediatrics, University of Illinois College of Medicine, Chicago, IL, United States; Children's Hospital of the University of Illinois, Chicago, IL, United States.
J Usha
JU
Raj
D000818:Animals; D000831:Animals, Newborn; D062186:Arterial Pressure / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D019175:DNA Methylation; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications*; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013997:Time Factors; D014162:Transfection; D066253:Vascular Remodeling
D019332:Endothelin-1; D056572:Histone Deacetylase Inhibitors; C583557:IGF1 protein, human; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D006655:Histone Deacetylases
DNA methylation; Endothelin-1; Histone deacetylase; IGF-1; Neonatal hypoxia; Pulmonary hypertension